Transneuronal degeneration is the death of neurons resulting from the disruption of input from or

output Output may refer to: * The information produced by a computer, see Input/output * An output state of a system, see state (computer science) * Output (economics), the amount of goods and services produced ** Gross output in economics, the valu ...

to other nearby

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s. It is an active excitotoxic process when a neuron is overstimulated by a neurotransmitter (most commonly glutamate) causing the dysfunction of that neuron (either damaging it or killing it) which drives neighboring neurons into metabolic deficit, resulting in rapid, widespread loss of neurons. This can be either anterograde or retrograde, indicating the direction of the degeneration relative to the original site of damage ( see types). There are varying causes for transneuronal degeneration such as brain

lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals. Types There is no de ...

s, disconnection syndromes, respiratory chain deficient neuron interaction, and lobectomies. Although there are different causes, transneuronal degeneration generally results in the same effects (whether they be cellular, dendritic, or axonal) to varying degrees. Transneuronal degeneration is thought to be linked to a number of diseases, most notably

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

, and researchers recently have been performing experiments with monkeys and rats, monitoring lesions in different parts of the body to study more closely how exactly the process works.

Types

Transneuronal degeneration can be grouped into two general categories: anterograde and retrograde.

Anterograde transneuronal degeneration

Anterograde transneuronal degeneration is degeneration caused by loss of inputs; it occurs when a neuron in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

is damaged and causes the degeneration of a postsynaptic neuron associated with a similar function as the

presynaptic neuron Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

. It is often termed "dying forward," and is also referred to as trans-synaptic degeneration. Anterograde degeneration can occur at a late stage of brain injury and result in diaschisis.

Retrograde transneuronal degeneration

Retrograde transneuronal degeneration is degeneration caused by loss of

trophic Trophic, from Ancient Greek τροφικός (''trophikos'') "pertaining to food or nourishment", may refer to: * Trophic cascade * Trophic coherence * Trophic egg * Trophic function * Trophic hormone * Trophic level index * Trophic level * ...

support from the target. It occurs in presynaptic cells that are sending inputs to injured postsynaptic cells. It is often termed "dying backward." This type of degeneration can be seen in

Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

. Loss of

Betz cell Betz cells (also known as pyramidal cells of Betz) are giant pyramidal cells (neurons) located within the fifth layer of the grey matter in the primary motor cortex. These neurons are the largest in the central nervous system, sometimes reaching 1 ...

s is a variable effect of this disease but the loss of these cells in this disease demonstrates the “dying-back” ( axonopathy) due to the changes in upper motor neurons.

Presentation

Associated diseases

Huntington's disease and multiple system atrophy

A study done shows that after excitotoxic injury to the

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

of adult rats, anterograde transneuronal degeneration occurs in the

substantia nigra pars reticulata The pars reticulata (SNpr) is a portion of the substantia nigra and is located lateral to the pars compacta. Most of the neurons that project out of the pars reticulata are inhibitory GABAergic neurons (i.e., these neurons release GABA, which is a ...

. This results in cell death that is non-apoptotic. More studies need to be done; however, it is hypothesized that this can be related to

and

multiple system atrophy Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by tremors, slow movement, muscle rigidity, postural instability (collectively known as parkinsonism), autonomic dysfunction and ataxia. This is caused by progr ...

in which there is major striatal neuronal loss followed by considerable loss of neurons in the substantia nigra pars reticulata.

Alzheimer's disease

The reorganization of cellular structures that results from transneuronal degeneration can be seen in

. It is hypothesized that anterograde transneuronal degeneration causes the

hyperphosphorylation Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural ...

of the

tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...

and redistributing those proteins from the axon to the dendrites, which begins the breakdown of routing and sorting mechanisms.

Cockayne syndrome

Cockayne syndrome Cockayne syndrome (CS), also called Neill-Dingwall syndrome, is a rare and fatal autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight ( photo ...

results from a mutation in genes that interfere with transcription-coupled repair of

nuclear Nuclear may refer to: Physics Relating to the nucleus of the atom: *Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics * Nuclear space *Nuclear ...

and

mitochondrial DNA Mitochondrial DNA (mtDNA and mDNA) is the DNA located in the mitochondrion, mitochondria organelles in a eukaryotic cell that converts chemical energy from food into adenosine triphosphate (ATP). Mitochondrial DNA is a small portion of the D ...

, replication, and transcription. Neuronal death is predominantly in the

cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...

, but this disease also causes

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

purkinje cell Purkinje cells or Purkinje neurons, named for Czech physiologist Jan Evangelista Purkyně who identified them in 1837, are a unique type of prominent, large neuron located in the Cerebellum, cerebellar Cortex (anatomy), cortex of the brain. Wi ...

s and causes them to have dystrophic dendrites. Loss of sensory receptors in the

cochlea The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus (cochlea), modiolus. A core component of the cochlea is the organ of Cort ...

, vestibules, and

retina The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...

result in

ganglion A ganglion (: ganglia) is a group of neuron cell bodies in the peripheral nervous system. In the somatic nervous system, this includes dorsal root ganglia and trigeminal ganglia among a few others. In the autonomic nervous system, there are ...

degeneration and transneuronal degeneration. Demyelination also results as

oligodendrocyte Oligodendrocytes (), also known as oligodendroglia, are a type of neuroglia whose main function is to provide the myelin sheath to neuronal axons in the central nervous system (CNS). Myelination gives metabolic support to, and insulates the axons ...

s and

Schwann cell Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include Satellite glial cell, satellite ...

s are killed.

Amyotrophic lateral sclerosis

Evidence supports the theory that

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

causes anterograde dengeneration of corticomotoneurons. The hyperexcitable corticomotoneurons drive anterior horn cells into metabolic deficit, resulting in cell degeneration and death. If this exocitotoxic process occurs rapidly, it results in a more rapid death of anterior horn cells resulting in lower motor neuron disease.

Causes

There are several different mechanisms by which transneuronal degeneration can occur. The technical cause of transneuronal degeneration is the death of neurons resulting from the disruption of input from or output to other nearby neurons.

Lesions

Anterograde and retrograde transneuronal degeneration is typically seen in humans around

s in the

limbic The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''P ...

, visual, or dentate-rubro-olivary pathways. Lesions to the brain cause pathological changes that can cause anterograde transneuronal degeneration and lead to system degeneration. Brain lesions create structural or transient deafferntation (the interruption or elimination of sensory nerve impulses by injuring or damaging sensory nerve fibers) because injury to the area causes a loss of excitatory input to other areas in the brain, causing them to be less responsive to stimuli. Delayed secondary transneuronal degeneration can also occur at a late stage after

brain injury Brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating trauma-induced damage. A common ...

because after the period of latency, neuroplastic rearrangement follows deafferentation. This deafferentation creates interruption of complex circuitry, which can lead to transneuronal structural degeneration. Although studies have shown that lesions can lead to transneuronal degeneration, lesions in the

somatic motor system Somatic may refer to: * Somatic (biology), referring to the cells of the body in contrast to the germ line cells ** Somatic cell, a non-gametic cell in a multicellular organism * Somatic nervous system, the portion of the vertebrate nervous syst ...

might not cause it. There is not much information on how transneuronal degeneration affects the somatic motor system . Anterograde transneuronal degeneration is not likely to happen since motor neurons are often exhibit convergence (receive input from wide variety of afferent systems). Transneuronal degeneration of lower motor neurons is not present after upper motor neuron lesions in stroke patients. In addition cortico spinal tract lesions do not cause anterograde transneuronal degeneration of spinal anterior horn cells.

Disconnection syndrome

Disconnection syndromes, defined as any neurologic disorder caused by an interruption in impulse transmission along cerebral fiber pathways, can cause white matter brain lesions, leading to secondary neuronal loss and transneuronal degeneration. Secondary neuronal loss occurs as a result in areas that are strongly connected with the severed tracts or restricted cortex during an

anterior temporal lobectomy Anterior temporal lobectomy (ATL) is the complete or partial removal of the anterior portion of the temporal lobe of the brain. The exact boundaries for removal can vary slightly in practice and between neurosurgeons. It is a treatment option for ...

Temporal lobe The temporal lobe is one of the four major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe is involved in pr ...

lesions also cause transneuronal degeneration, the effects of which can be seen in the fornix, mammillary bodies, and contralateral

Respiratory chain-deficient neuron development

It has recently been shown that transneuronal degeneration can also be caused after respiratory chain-deficient neurons develop from ''

de novo De novo (Latin, , used in English to mean 'from the beginning', 'anew') may refer to: Science and computers * ''De novo'' mutation, a new germline mutation not inherited from either parent * ''De novo'' protein design, the creation of a protei ...

'' mitochondrial DNA mutations, which are normally associated with mammalian ageing. The respiratory chain-deficient neurons have adverse effect on normal adjacent neurons, inducing death by means of transneuronal degeneration. Transneuronal degeneration in these cases is accelerated during the ageing process since other cellular maintenance systems are already damaged as well as in the presence of

mitochondrial disease Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy o ...

, where non-neuronal cells like

glial cells Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...

and

astrocytes Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of end ...

also have respiratory chain deficiency. This also means that transneuronal degeneration could enhance the consequences of patients with degenerative processes like Alzheimer’s disease ( see associated diseases) because of the neuronal damage from lesions already present. Since neurons are linked in trophic units, this transneuronal degeneration can lead to substantial cell death over time.

Lobectomy

Removing portions of an animal's brain can be performed to induce transneuronal degeneration. Transneuronal degeneration results after a sudden massive loss of input from the

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex (OF ...

after it was removed. Removal of the

left hemisphere The lateralization of brain function (or hemispheric dominance/ lateralization) is the tendency for some neural functions or cognitive processes to be specialized to one side of the brain or the other. The median longitudinal fissure separates ...

in monkeys caused retrograde transneuronal degeneration of the

retinal ganglion cell A retinal ganglion cell (RGC) is a type of neuron located near the inner surface (the ganglion cell layer) of the retina of the eye. It receives visual information from photoreceptor cell, photoreceptors via two intermediate neuron types: Bipolar ...

s that affected mainly the foveal rim. This also resulted in reduction in the number of

s in the parvocellular and magnocellular layers. Evidence of retinal ganglion cell loss consistent with retrograde trans-synaptic degeneration has also been demonstrated in-vivo with optical coherence tomography in humans.

Pathophysiology

Cellular

Transneuronal degeneration creates many telling characteristics in affected cells. The cells themselves tend to shrink, which is best seen in cytoplasmic and nuclear shrinkage. The nucleic acid material becomes reorganized and the distinction between

nucleus Nucleus (: nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucleu ...

and

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

becomes diminished. The

nuclear membrane The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer polar membrane, membranes that in eukaryotic cells surround the Cell nucleus, nucleus, which encloses the genome, genetic material. The nuclear envelope con ...

often becomes detached. This causes an increase in

electron density Electron density or electronic density is the measure of the probability of an electron being present at an infinitesimal element of space surrounding any given point. It is a scalar quantity depending upon three spatial variables and is typical ...

in the cytoplasm due to the increased concentration of cytoplasmic and nucleic contents. This nucleus degeneration occurs in a later stage than the cytoplasmic effects and results in an increase of condensed

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...

aggregation. The

nucleolus The nucleolus (; : nucleoli ) is the largest structure in the cell nucleus, nucleus of eukaryote, eukaryotic cell (biology), cells. It is best known as the site of ribosome biogenesis. The nucleolus also participates in the formation of signa ...

also gets replaced with a large homogenous cluster of electron dense material. There appears to be an increase in free

ribosome Ribosomes () are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (messenger RNA translation). Ribosomes link amino acids together in the order s ...

s, though the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

does not seem to lose any ribosomes.

Mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

, endoplasmic reticulum,

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...

and multivesicular bodies all appear to swell, though this can be best seen in the mitochondria which appear to swell first.

Lysosome A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

s do not appear to be affected, but there is an appearance of large, empty vacuoles in the cytoplasm.

Dendritic and axonal

Transneuronal degeneration affects

dendrites A dendrite (from Greek δένδρον ''déndron'', "tree") or dendron is a branched cytoplasmic process that extends from a nerve cell that propagates the electrochemical stimulation received from other neural cells to the cell body, or soma ...

and

axons An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see spelling differences) is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action pot ...

as well. There is evident shrinkage in the main dendritic shafts. The concentration of free ribosomes increases and there is a noticeable increase in the granular background of the cytoplasm. In the initial parts of the dendrites, mitochondrial swelling and dilation can be seen. This swelling can also be seen in the endoplasmic reticulum and the golgi apparatuses. The most notable effect is the dense packing of neurotubules (neuronal microtubules). In severely affected cells, this packing greatly reduces the intertubular space to no wider than the tubule. In examining the cells, the tubular outline becomes more pronounced. In axons, similar effects can be seen. There is swelling in mitochondria and other membrane bound

organelles In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...

. There is also a marked increase in cytoplasmic granularity and the dense packing of the neurotubules. Despite these alterations, synaptic specializations appear unchanged.

Degrees of degeneration

There are varying degrees of degeneration. In mild degeneration the cytoplasmic areas shrinks and increases in density and mitochondria swell. However, the endomplasmic reticulum and the golgi apparatuses appear unchanged. The nuclear membrane appears intact, but there is some loss in differentiation in nuclear material. In more severely affected cells, the separation between the cytoplasm and nucleus diminishes significantly, causing the cytoplasm to become even more dense and have an increase in electron density.

Neuroglia Glia, also called glial cells (gliocytes) or neuroglia, are non- neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...

cells are only affected in severe cases. They fill in the spaces that have been diminished due to the loss or

atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...

of the dendritic terminals.

Astrocytes Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of end ...

and

microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...

cells digest the decaying organelles and dying neurons through

phagocytosis Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...

Research

Eye enucleation in macaque monkeys

Many studies have been done on monkeys and rats to see the development of transneuronal degeneration after damage to various parts of the brain.

Enucleation of the eye Enucleation is the removal of the eye that leaves the eye muscles and remaining orbital contents intact. This type of ocular surgery is indicated for a number of ocular tumors, in eyes that have sustained severe trauma, and in eyes that are oth ...

creates transneuronal degeneration. A study was done performing enucleation of the eye on macaque monkeys to determine if this degeneration would lead to loss of neurons. It was the first experiment done on adult animals to show evidence of loss of neurons after one year, a long survival period for those affected cells. The degeneration led to cell shrinkage and cell death, and these symptoms were more profound after one year than during the first four months.

Olfactory removal in rats

Another study being done is on rats in which the

is removed has resulted in neurons in the primary

olfactory cortex The olfactory system, is the sensory system used for the sense of smell (olfaction). Olfaction is one of the special senses directly associated with specific organs. Most mammals and reptiles have a main olfactory system and an accessory olfact ...

becoming argyrophilic in silver infused preparations. This allows the researchers to view the cells under

electron microscope An electron microscope is a microscope that uses a beam of electrons as a source of illumination. It uses electron optics that are analogous to the glass lenses of an optical light microscope to control the electron beam, for instance focusing it ...

s and see that these cells rapidly degenerate. The first signs of degeneration seen after the removal of the bulb was mitochondrial swelling and then an increase in electron density in the cytoplasm. Nuclear changes are seen later in which chromatin condenses and the

becomes replaced with large clusters of electron dense material. Once the degeneration has advanced far enough, ribosomes begin to disperse throughout the cell. Some cells are then phagocytosed by astrocytes and microglia. This study showed that the most cells affected by the

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...

were not directly connected to the olfactory bulb, but were located closer more superficially. This provided them with them hypothesis that olfactory bulb removal results in transneuronal deafferentation as a result of the massive sudden loss of input from the removed brain tissue.

Unilateral perforant pathway transection in rats and mice

Unilateral perforant pathway transection is a method to study how transneuronal degeneration results from denervation in the Central Nervous System. Studies are still being done to solidify to connection between candidate molecules creating changes in the central nervous system and postleisonal changes. Current studies in rats and mice have provided evidence that microglia cells contribute to transneuronal degeneration of

parvalbumin Parvalbumin (PV) is a calcium-binding protein with low molecular weight (typically 9–11 kDa). In humans, it is encoded by the ''PVALB'' gene. It is a member of the albumin family; it is named for its size (''parv-'', from Latin ' which means " ...

-positive dendrites. Denervation in the entorhinal-hippicampal area of control in mice brains resulted in anterograde neuronal degeneration. This resulted in a smaller microglia response in that area when stimulated in comparison to the wild type group.