The Role of Axonal Transport in Neurodegenerative Disease Spread: A Meta-Analysis of Experimental and Clinical Poliomyelitis Compares with Amyotrophic Lateral Sclerosis

Brooks, Benjamin Rix

doi:10.1017/s0317167100032625

Cited by 47 publications

(46 citation statements)

References 5 publications

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“…3). Similar results have been shown by Brooks et al 21 , and corroborate the findings that neuronal degeneration occurs more quickly in contiguous areas and that rostral-caudal involvement is faster than caudal-rostral spread, possibly due to involvement of axonal transport 21,24 . Bulbar and spinal-onset ALS predominated in men in our series; moreover, when considered in any time of the evolution, this predominance of men over women persists.…”

Section: Discussionsupporting

confidence: 88%

Amyotrophic lateral sclerosis: clinical analysis of 78 cases from Fortaleza (Northeastern Brazil)

Castro-Costa

Oriá

Machado-Filho

et al. 1999

Arq. Neuro-Psiquiatr.

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-We report on the clinical characteristics of amyotrophic lateral sclerosis (ALS) in Fortaleza (Northeastern Brazil). For this, we analyzed retrospectively (from 1980 to 1999) 78 cases of ALS from the Service of Neurology of the University Hospital of Fortaleza diagnosed clinically and laboratorially (EMG, muscle biopsy, myelography, blood biochemistry, muscle enzymes and cranio-cervical X-ray). The results showed that they were mostly sporadic ALS (76/78), and they were divided into definite (n= 36), probable (n= 20), possible (n= 15) and suspected (n= 7), according to the level of diagnostic certainty. They were also subdivided into juvenile (n= 17), early-onset adult (n= 18), age-specific (n= 39) and late-onset (n= 4) groups. Clinically, they presented as initials symptoms, principally, asymmetrical (30/78) and symmetrical (24/78) weakness of extremities, besides bulbar signs, fasciculations, and atrophy. Curiously, pain as first symptom occurred in an expressive fashion (17/78). The predominant initial anatomic site, in this series, was the spinal cord, and mainly affecting the arms. As to the symptom accrual from region to region, this occurs more quickly in contiguous areas, and fasciculations are predominant when bulbar region was associated.KEY WORDS: ALS, sporadic, early-onset, pain, anatomy, symptom accrual, fasciculations. Esclerose lateral amiotrófica: análise clínica de 78 casos de Fortaleza (Nordeste Brasileiro)RESUMO -Descrevemos as características clínicas da esclerose lateral amiotrófica (ELA) em Fortaleza (Nordeste Brasileiro). Para isso, fizemos uma análise retrospectiva (de 1980 a 1999) de 78 casos de ELA do Serviço de Neurologia do Hospital Universitário de Fortaleza, diagnosticados do ponto de vista clínico e laboratorial (EMG, biópsia de músculo, mielografia, análises hematológica e bioquímica, e raio X da junção crânio-cervical). Os resultados mostraram que esses casos eram principalmente da forma esporádica (76/78), e estes foram divididos, de acordo com o nível de certeza diagnóstica, em definidos (n= 36), prováveis (n= 20), possíveis (n= 15) e suspeitos (n= 7). Eles foram também subdivididos nos grupos juvenil (n= 17), adulto jovem (n= 18), idadeespecífico (n= 39) e tardio (n= 4). Clinicamente, os principais sintomas iniciais foram fraqueza assimétrica (38/ 78) e simétrica (24/78) das extremidades, além de sinais bulbares, fasciculações e atrofia. Curiosamente, dor como sintoma inicial ocorria de maneira expressiva (17/78). O local anatômico inicial predominante foi, nessa série, a medula espinhal, afetando principalmente os braços. O avanço regional de sintomas ocorreu mais rapidamente em áreas contíguas, e as fasciculações eram predominantes quando a região bulbar estava associada. PALAVRAS-CHAVE: ELA, esporádica, início precoce, dor, anatomia, avanço dos sintomas, fasciculações.Amyotrophic lateral sclerosis (ALS) is a condition of undetermined cause, which affects the anterior horn cells and the corticospinal tract.The etiology is manifold so that different causes have been...

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Section: Discussionsupporting

confidence: 88%

Amyotrophic lateral sclerosis: clinical analysis of 78 cases from Fortaleza (Northeastern Brazil)

Castro-Costa

Oriá

Machado-Filho

et al. 1999

Arq. Neuro-Psiquiatr.

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“…This toxic TDP-43 protein may be transported through the axon and, via synaptic contacts [24], be transmitted from the primarily involved cortical Betz cells to hitherto uninvolved neurons, where it could then contribute to the renewed dysregulation of TDP-43 [15, 22, 35, 42, 43, 50, 62]. This line of thinking receives support from the combination of (1) the absence of pTDP-43 immunoreactivity in nerve cells located directly next to the primarily involved Betz cells in layer Vb (Fig.…”

Section: Discussionmentioning

confidence: 99%

Pathological TDP-43 changes in Betz cells differ from those in bulbar and spinal α-motoneurons in sporadic amyotrophic lateral sclerosis

et al. 2016

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Two nerve cells types, Betz cells in layer Vb of the primary motor neocortex and α-motoneurons of the lower brainstem and spinal cord, become involved at the beginning of the pathological cascade underlying sporadic amyotrophic lateral sclerosis (sALS). In both neuronal types, the cell nuclei forfeit their normal (non-phosphorylated) expression of the 43-kDa transactive response DNA-binding protein (TDP-43). Here, we present initial evidence that in α-motoneurons the loss of normal nuclear TDP-43 expression is followed by the formation of phosphorylated TDP-43 aggregates (pTDP-43) within the cytoplasm, whereas in Betz cells, by contrast, the loss of normal nuclear TDP-43 expression remains mostly unaccompanied by the development of cytoplasmic aggregations. We discuss some implications of this phenomenon of nuclear clearing in the absence of cytoplasmic inclusions, namely, abnormal but soluble (and, thus, probably toxic) cytoplasmic TDP-43 could enter the axoplasm of Betz cells, and following its transmission to the corresponding α-motoneurons in the lower brainstem and spinal cord, possibly contribute in recipient neurons to the dysregulation of the normal nuclear protein. Because the cellular mechanisms that possibly inhibit the aggregation of TDP-43 in the cytoplasm of involved Betz cells are unknown, insight into such mechanisms could disclose a pathway by which the development of aggregates in this cell population could be accelerated, thereby opening an avenue for a causally based therapy.

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“…Neurodegeneration starts locally and spreads from one myotome segment to the segment next to it (53)(54)(55). This domino-like propagation of the pathology has previously been taken as evidence for a viral infection accompanying the disease (56).…”

Section: Discussionmentioning

confidence: 99%

Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state

Lindberg

Tibell

Oliveberg

2002

Proc. Natl. Acad. Sci. U.S.A.

180

177

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More than 100 point mutations of the superoxide scavenger Cu͞Zn superoxide dismutase (SOD; EC 1.15.1.1) have been associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, these mutations are scattered throughout the protein and provide no clear functional or structural clues to the underlying disease mechanism. Therefore, we undertook to look for foldingrelated defects by comparing the unfolding behavior of five ALS-associated mutants with distinct structural characteristics: A4V at the interface between the N and C termini, C6F in the hydrophobic core, D90A at the protein surface, and G93A and G93C, which decrease backbone flexibility. With the exception of the disruptive replacements A4V and C6F, the mutations only marginally affect the stability of the native protein, yet all mutants share a pronounced destabilization of the metal-free apo state: the higher the stability loss, the lower the mean survival time for ALS patients carrying the mutation. Thus organism-level pathology may be directly related to the properties of the immature state of a protein rather than to those of the native species.A myotrophic lateral sclerosis (ALS) is a motor neuron syndrome where a sub group of 3-6% has been associated with a diverse set of mutations in the superoxide scavenger Cu͞Zn superoxide dismutase (SOD; 1.15.1.1) (1, 2). Interestingly, several of these mutations show perfectly native-like in vivo activity (3, 4) and metal coordination (5). As an alternative cause of disease, transgenic mouse models suggest that ALS arises through an adverse, and yet-unidentified, side reaction of the mutated protein causing cytotoxicity. Mice devoid of SOD retain normal motor function (6), as do mice overexpressing wild-type SOD. In contrast, mice expressing high levels of mutant human SOD in addition to endogenous SOD show neural damage. The collective evidence suggests that mutant SOD has gained a cytopathogenic function (7,8). Models for how the neurodegenerating toxicity arise include the following: (i) enzymatic side-reactions in catalytically promiscuous SOD mutants producing increased levels of oxidative compounds such as hydroxyl radicals (9-11) and peroxynitrite (12), (ii) release of free Cu ions (13), (iii) aberrant binding of SOD to other proteins (14), (iv) binding of mutant SOD to heat shock proteins (15, 16) with the subsequent prevention of their antiapoptotic function (16), (v) altered redox regulation (17), and (vi) formation of toxic SOD aggregates (18)(19)(20). Evidence that could potentially distinguish between these models was recently provided from mice lacking the metal-loading chaperone CCS (copper chaperone for SOD; ref. 21). The chaperone is essential for incorporating the copper ion and, hence, to gain the native protein. When the CCS gene was ablated, the ALS-associated mutations were observed to still provoke the disease, indicating that a copper-free precursor state of SOD causes neurotoxicity (21). Along this line, a broad spectrum of mechanistic scenarios is implicated...

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The Role of Axonal Transport in Neurodegenerative Disease Spread: A Meta-Analysis of Experimental and Clinical Poliomyelitis Compares with Amyotrophic Lateral Sclerosis

Cited by 47 publications

References 5 publications

Amyotrophic lateral sclerosis: clinical analysis of 78 cases from Fortaleza (Northeastern Brazil)

Amyotrophic lateral sclerosis: clinical analysis of 78 cases from Fortaleza (Northeastern Brazil)

Pathological TDP-43 changes in Betz cells differ from those in bulbar and spinal α-motoneurons in sporadic amyotrophic lateral sclerosis

Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state

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