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Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?

Kanouchi T, Ohkubo T, Yokota T - J. Neurol. Neurosurg. Psychiatr. (2012)

Bottom Line: The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system.Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS.Furthermore, the concept of 'propagation' is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan.

ABSTRACT
Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt-Jakob disease. The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system. Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS. The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects. Furthermore, the concept of 'propagation' is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool.

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Related in: MedlinePlus

Onset and regional spread mechanisms of amyotrophic lateral sclerosis (ALS) lesion. Symptom is initiated by focal neuronal change, the onset mechanism of which exists in every motor neuron (A–a), or is limited to the affected neuron (A–b). Regional spread of symptoms may be caused by summation of the increased number of the symptomatic or hit neurons. If the spread mechanism of ALS lesion is explained by propagation, it is classified as local and contiguous type (B–a) or remote and non-contiguous type (B–b). The contiguous type propagation is based on cell to cell transfer of disease property between the neurons proximate to each other and has a radial and horizontal vector of spread. The non-contiguous, trans-synaptic type propagation includes anterograde spread (dying forward) or retrograde degeneration (dying back) of neural networks. The non-contiguous non-synaptic type propagation includes remote transfer of the toxic molecule through blood and CSF.
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fig1: Onset and regional spread mechanisms of amyotrophic lateral sclerosis (ALS) lesion. Symptom is initiated by focal neuronal change, the onset mechanism of which exists in every motor neuron (A–a), or is limited to the affected neuron (A–b). Regional spread of symptoms may be caused by summation of the increased number of the symptomatic or hit neurons. If the spread mechanism of ALS lesion is explained by propagation, it is classified as local and contiguous type (B–a) or remote and non-contiguous type (B–b). The contiguous type propagation is based on cell to cell transfer of disease property between the neurons proximate to each other and has a radial and horizontal vector of spread. The non-contiguous, trans-synaptic type propagation includes anterograde spread (dying forward) or retrograde degeneration (dying back) of neural networks. The non-contiguous non-synaptic type propagation includes remote transfer of the toxic molecule through blood and CSF.

Mentions: Disease onset and disease progression are thought to have a different mechanism. Because the motor symptoms of ALS are usually initiated in one or two highly localised sites, the motor symptoms and the responsible lesions always spread regionally as the disease progresses. Many neurologists have thought that regional spread of the symptoms is just one aspect of disease progression in ALS because ALS is a systemic disease that eventually involves the entire UMN and LMN systems, and every motor neuron in ALS ubiquitously has a cause of disease. The most easily understood example is familial ALS with mutations in SOD1 or TDP-43, in which every motor neuron and glial cell has a chromosomal genetic defect that causes motoneuronal cell death (figure 1A–a). For the initial onset, in sporadic as well as familial ALS, molecular change most likely predates clinical onset. A motor neuron becomes symptomatic when the accumulated molecular pathology, including increased pathogenic protein aggregates, exceeds a certain threshold. In sporadic cases, the multifocal hit hypothesis has a different mechanism but represents a similar phenotype in which an acquired defect in chromatin, DNA, RNA or proteins (such as epigenetic alternation, a somatic DNA mutation, RNA editing error or misfolding of proteins possibly due to ageing effects or various environmental stressors) occurs randomly in each cell, and these defects accumulate and converge to initiate the pathogenic process (figure 1A–b). The multifocal hit hypothesis (figure 1A–b) is different from the ubiquitous change mechanism (figure 1A–a) in that the molecular change occurs in individual cells, and unaffected cells do not have any molecular defect. In both mechanisms, the region of initiation may be determined by a stochastic hit but there is a vulnerability among the motoneurons resulting in more frequent focal involvement of the tongue and distal limb muscles in the early stage. These two schemas shown in figure 1A–a and figure1A–b are a possible onset mechanism of ALS but the regional spread of the motor symptoms as a disease progression can also be explained by just summation of the increased number of symptomatic or hit neurons by the same mechanism without following propagative pathology.


Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?

Kanouchi T, Ohkubo T, Yokota T - J. Neurol. Neurosurg. Psychiatr. (2012)

Onset and regional spread mechanisms of amyotrophic lateral sclerosis (ALS) lesion. Symptom is initiated by focal neuronal change, the onset mechanism of which exists in every motor neuron (A–a), or is limited to the affected neuron (A–b). Regional spread of symptoms may be caused by summation of the increased number of the symptomatic or hit neurons. If the spread mechanism of ALS lesion is explained by propagation, it is classified as local and contiguous type (B–a) or remote and non-contiguous type (B–b). The contiguous type propagation is based on cell to cell transfer of disease property between the neurons proximate to each other and has a radial and horizontal vector of spread. The non-contiguous, trans-synaptic type propagation includes anterograde spread (dying forward) or retrograde degeneration (dying back) of neural networks. The non-contiguous non-synaptic type propagation includes remote transfer of the toxic molecule through blood and CSF.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3368493&req=5

fig1: Onset and regional spread mechanisms of amyotrophic lateral sclerosis (ALS) lesion. Symptom is initiated by focal neuronal change, the onset mechanism of which exists in every motor neuron (A–a), or is limited to the affected neuron (A–b). Regional spread of symptoms may be caused by summation of the increased number of the symptomatic or hit neurons. If the spread mechanism of ALS lesion is explained by propagation, it is classified as local and contiguous type (B–a) or remote and non-contiguous type (B–b). The contiguous type propagation is based on cell to cell transfer of disease property between the neurons proximate to each other and has a radial and horizontal vector of spread. The non-contiguous, trans-synaptic type propagation includes anterograde spread (dying forward) or retrograde degeneration (dying back) of neural networks. The non-contiguous non-synaptic type propagation includes remote transfer of the toxic molecule through blood and CSF.
Mentions: Disease onset and disease progression are thought to have a different mechanism. Because the motor symptoms of ALS are usually initiated in one or two highly localised sites, the motor symptoms and the responsible lesions always spread regionally as the disease progresses. Many neurologists have thought that regional spread of the symptoms is just one aspect of disease progression in ALS because ALS is a systemic disease that eventually involves the entire UMN and LMN systems, and every motor neuron in ALS ubiquitously has a cause of disease. The most easily understood example is familial ALS with mutations in SOD1 or TDP-43, in which every motor neuron and glial cell has a chromosomal genetic defect that causes motoneuronal cell death (figure 1A–a). For the initial onset, in sporadic as well as familial ALS, molecular change most likely predates clinical onset. A motor neuron becomes symptomatic when the accumulated molecular pathology, including increased pathogenic protein aggregates, exceeds a certain threshold. In sporadic cases, the multifocal hit hypothesis has a different mechanism but represents a similar phenotype in which an acquired defect in chromatin, DNA, RNA or proteins (such as epigenetic alternation, a somatic DNA mutation, RNA editing error or misfolding of proteins possibly due to ageing effects or various environmental stressors) occurs randomly in each cell, and these defects accumulate and converge to initiate the pathogenic process (figure 1A–b). The multifocal hit hypothesis (figure 1A–b) is different from the ubiquitous change mechanism (figure 1A–a) in that the molecular change occurs in individual cells, and unaffected cells do not have any molecular defect. In both mechanisms, the region of initiation may be determined by a stochastic hit but there is a vulnerability among the motoneurons resulting in more frequent focal involvement of the tongue and distal limb muscles in the early stage. These two schemas shown in figure 1A–a and figure1A–b are a possible onset mechanism of ALS but the regional spread of the motor symptoms as a disease progression can also be explained by just summation of the increased number of symptomatic or hit neurons by the same mechanism without following propagative pathology.

Bottom Line: The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system.Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS.Furthermore, the concept of 'propagation' is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan.

ABSTRACT
Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt-Jakob disease. The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system. Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS. The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects. Furthermore, the concept of 'propagation' is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool.

Show MeSH
Related in: MedlinePlus