Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions

Motor unit number estimation (MUNE) is an electrophysiological method designed to quantify motor unit loss in target muscles of interest. Most of the techniques are noninvasive and are therefore well suited for longitudinal monitoring. In this brief review, we describe the more commonly used techniques and their applications in amyotrophic lateral sclerosis, poliomyelitis, spinal muscular atrophy and hereditary sensorimotor neuropathies. Findings in some of these studies offer important pathophysiological insights. Since conventional electrophysiologic methods are not sensible measures of motor neuronal loss, MUNE could play a potentially important role in the diagnosis, monitoring of disease progression and response to treatment in neuromuscular diseases in which motor unit loss is a major feature.

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Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease

Journal of Virology ◽

10.1128/jvi.01165-15 ◽

2015 ◽

Vol 89 (15) ◽

pp. 7660-7672 ◽

Cited By ~ 25

Author(s):

Leonardo M. Cortez ◽

Jody Campeau ◽

Grant Norman ◽

Marian Kalayil ◽

Jacques Van der Merwe ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Bile Acids ◽

Prion Disease ◽

Prion Diseases ◽

Neuronal Loss ◽

Disease Models ◽

Orally Bioavailable ◽

Prion Conversion ◽

Lateral Sclerosis

ABSTRACTPrion diseases are fatal neurodegenerative disorders associated with the conversion of cellular prion protein (PrPC) into its aberrant infectious form (PrPSc). There is no treatment available for these diseases. The bile acids tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA) have been recently shown to be neuroprotective in other protein misfolding disease models, including Parkinson's, Huntington's and Alzheimer's diseases, and also in humans with amyotrophic lateral sclerosis. Here, we studied the therapeutic efficacy of these compounds in prion disease. We demonstrated that TUDCA and UDCA substantially reduced PrP conversion in cell-free aggregation assays, as well as in chronically and acutely infected cell cultures. This effect was mediated through reduction of PrPScseeding ability, rather than an effect on PrPC. We also demonstrated the ability of TUDCA and UDCA to reduce neuronal loss in prion-infected cerebellar slice cultures. UDCA treatment reduced astrocytosis and prolonged survival in RML prion-infected mice. Interestingly, these effects were limited to the males, implying a gender-specific difference in drug metabolism. Beyond effects on PrPSc, we found that levels of phosphorylated eIF2α were increased at early time points, with correlated reductions in postsynaptic density protein 95. As demonstrated for other neurodegenerative diseases, we now show that TUDCA and UDCA may have a therapeutic role in prion diseases, with effects on both prion conversion and neuroprotection. Our findings, together with the fact that these natural compounds are orally bioavailable, permeable to the blood-brain barrier, and U.S. Food and Drug Administration-approved for use in humans, make these compounds promising alternatives for the treatment of prion diseases.IMPORTANCEPrion diseases are fatal neurodegenerative diseases that are transmissible to humans and other mammals. There are no disease-modifying therapies available, despite decades of research. Treatment targets have included inhibition of protein accumulation, clearance of toxic aggregates, and prevention of downstream neurodegeneration. No one target may be sufficient; rather, compounds which have a multimodal mechanism, acting on different targets, would be ideal. TUDCA and UDCA are bile acids that may fulfill this dual role. Previous studies have demonstrated their neuroprotective effects in several neurodegenerative disease models, and we now demonstrate that this effect occurs in prion disease, with an added mechanistic target of upstream prion seeding. Importantly, these are natural compounds which are orally bioavailable, permeable to the blood-brain barrier, and U.S. Food and Drug Administration-approved for use in humans with primary biliary cirrhosis. They have recently been proven efficacious in human amyotrophic lateral sclerosis. Therefore, these compounds are promising options for the treatment of prion diseases.

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Reduced brainN-acetyl-aspartate in frontal lobes suggests neuronal loss in patients with amyotrophic lateral sclerosis

Neurological Research ◽

10.1080/01616412.1996.11740412 ◽

1996 ◽

Vol 18 (3) ◽

pp. 241-243 ◽

Cited By ~ 24

Author(s):

Maurice Giroud ◽

Paul Walker ◽

David Bernard ◽

Martine Lemesle ◽

Didier Martin ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neuronal Loss ◽

Frontal Lobes ◽

Lateral Sclerosis

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Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

Life Science Alliance ◽

10.26508/lsa.202000764 ◽

2021 ◽

Vol 4 (4) ◽

pp. e202000764

Author(s):

Arun Pal ◽

Benedikt Kretner ◽

Masin Abo-Rady ◽

Hannes Glaβ ◽

Banaja P Dash ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Loss Of Function ◽

Dna Double Strand Breaks ◽

Hexanucleotide Repeat ◽

Rna Foci ◽

Repeat Expansions ◽

Organelle Motility ◽

Trafficking Defects ◽

Induced Pluripotent ◽

Lateral Sclerosis

Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient—albeit to a smaller extent—to induce premature distal axonal trafficking deficits and increased DSBs.

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Neuropathology of Speech Network Distinguishes Bulbar From Nonbulbar Amyotrophic Lateral Sclerosis

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlz130 ◽

2019 ◽

Vol 79 (3) ◽

pp. 284-295

Author(s):

Sanjana Shellikeri ◽

Julia Keith ◽

Sandra E Black ◽

Lorne Zinman ◽

Yana Yunusova

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Dna Binding ◽

Cognitive Deficits ◽

Regional Distribution ◽

Neuronal Loss ◽

Dna Binding Protein ◽

Motor Functions ◽

Bulbar Symptoms ◽

Bulbar Onset ◽

Lateral Sclerosis

Abstract Bulbar amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative subtype affecting speech and swallowing motor functions as well as associated with the burden of cognitive deficits. The neuroanatomical underpinnings of bulbar ALS are not well understood. The aim of this study was to compare neuropathology of the speech network (SpN) between 3 cases of bulbar-onset ALS (bALS), 3 cases of spinal-onset ALS (sALS) with antemortem bulbar ALS (sALSwB) against 3 sALS without antemortem bulbar ALS (sALSnoB) and 3 controls. Regional distribution and severity of neuronal loss, TDP-43 (transactive response DNA-binding protein of 43 kDa), and tau proteinopathy were examined. All 3 bALS cases showed marked neuronal loss and severe proteinopathy across most SpN regions; sALSwB cases showed no neuronal loss but mild and variable TDP-43 pathology in focal regions; sALSnoB cases demonstrated an absence of pathology. Two bALS cases had coexisting tauopathy in SpN regions, which was not noted in any sALS cases. The findings suggested that bALS may have a distinct neuropathological signature characterized by marked neuronal loss and polypathology in the SpN. Milder TDP-43 pathology in the SpN for sALSwB cases suggested a link between severity of bulbar ALS and SpN damage. Findings support a clinicopathologic link between bulbar symptoms and pathology in the SpN.

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C9orf72 repeat expansions in South Africans with amyotrophic lateral sclerosis

Journal of the Neurological Sciences ◽

10.1016/j.jns.2019.04.026 ◽

2019 ◽

Vol 401 ◽

pp. 51-54 ◽

Cited By ~ 2

Author(s):

Melissa Nel ◽

Gloudi M. Agenbag ◽

Franclo Henning ◽

Helen M. Cross ◽

Alina Esterhuizen ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

South Africans ◽

Repeat Expansions ◽

Lateral Sclerosis

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Multiple System Atrophy and Amyotrophic Lateral Sclerosis in a Family With Hexanucleotide Repeat Expansions inC9orf72

JAMA Neurology ◽

10.1001/jamaneurol.2013.5762 ◽

2014 ◽

Vol 71 (6) ◽

pp. 771 ◽

Cited By ~ 40

Author(s):

Jill S. Goldman ◽

Catarina Quinzii ◽

Jane Dunning-Broadbent ◽

Cheryl Waters ◽

Hiroshi Mitsumoto ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Multiple System Atrophy ◽

Hexanucleotide Repeat ◽

Repeat Expansions ◽

Lateral Sclerosis

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CSF chitinase proteins in amyotrophic lateral sclerosis

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-320442 ◽

2019 ◽

Vol 90 (11) ◽

pp. 1215-1220 ◽

Cited By ~ 14

Author(s):

Alexander G Thompson ◽

Elizabeth Gray ◽

Alexander Bampton ◽

Dominika Raciborska ◽

Kevin Talbot ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Area Under The Curve ◽

Neuronal Loss ◽

Progression Rate ◽

Healthy Controls ◽

Reactive Protein ◽

Classifier Performance ◽

Disease Progression Rate ◽

Csf Levels ◽

Lateral Sclerosis

ObjectiveTo evaluate the classifier performance, clinical and biochemical correlations of cerebrospinal fluid (CSF) levels of the chitinase proteins Chitotriosidase-1 (CHIT1), Chitinase-3-like protein 1 (CHI3L1) and Chitinase-3-like protein 2 (CHI3L2) in amyotrophic lateral sclerosis (ALS).MethodsCSF levels of CHIT1, CHI3L1, CHI3L2, phosphorylated neurofilament heavy chain (pNFH) and C-reactive protein were measured by ELISA in a longitudinal cohort of patients with ALS (n=82), primary lateral sclerosis (PLS, n=10), ALS-mimic conditions (n=12), healthy controls (n=25) and asymptomatic carriers of ALS-causing genetic mutations (AGC; n=5).ResultsCSF CHIT1, CHI3L1 and CHI3L2 were elevated in patients with ALS compared with healthy controls (p<0.001) and ALS-mimics (CHIT1, p<0.001; CHI3L1, p=0.017; CHI3L2, p<0.001). CHIT1 and CHI3L2 were elevated in ALS compared with PLS (CHIT1, p=0.021; CHI3L1, p=0.417; CHI3L2, p<0.001). Chitinase levels were similar in AGCs and healthy controls. Chitinase proteins distinguished ALS from healthy controls (area under the curve (AUC): CHIT1 0.92; CHI3L1 0.80; CHI3L2 0.90), mimics (AUC: CHIT1 0.84; CHI3L1 0.73; CHI3L2 0.88) and, to a lesser extent, PLS (AUC: CHIT 0.73; CHI3L1 0.51; CHI3L2 0.82) but did not outperform pNFH. CHIT1 and CHI3L2 correlated with disease progression rate (Pearson’s r=0.49, p<0.001; r=0.42, p<0.001, respectively). CHI3L1 correlated with degree of cognitive dysfunction (r=−0.25, p=0.038). All chitinases correlated with pNFH. CHIT1 levels were associated with survival in multivariate models. Chitinase levels were longitudinally stable.ConclusionsCSF chitinase proteins may have limited value as independent diagnostic and stratification biomarkers in ALS, but offer a window into non-autonomous mechanisms of motor neuronal loss in ALS, specifically in assessing response to therapies targeting neuroinflammatory pathways.

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Identification of GGC repeat expansion in the NOTCH2NLC gene in amyotrophic lateral sclerosis

Neurology ◽

10.1212/wnl.0000000000010945 ◽

2020 ◽

Vol 95 (24) ◽

pp. e3394-e3405 ◽

Cited By ~ 1

Author(s):

Yanchun Yuan ◽

Zhen Liu ◽

Xuan Hou ◽

Wanzhen Li ◽

Jie Ni ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mainland China ◽

Repeat Expansion ◽

Fisher Exact Test ◽

Healthy Controls ◽

Exact Test ◽

Repeat Expansions ◽

Neuronal Intranuclear Inclusion ◽

Electrophysiologic Studies ◽

Lateral Sclerosis

ObjectiveTo determine whether the GGC repeats in the NOTCH2NLC gene contribute to amyotrophic lateral sclerosis (ALS).MethodsIn this study, 545 patients with ALS and 1,305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes (including C9ORF72 and ATXN2) and polynucleotide repeat expansions in NOP56 and AR genes were excluded. Repeat-primed PCR and GC-rich PCR were performed to determine the GGC repeat size in NOTCH2NLC. Systematic and targeted clinical evaluations and investigations, including skin biopsy and dynamic electrophysiologic studies, were conducted in the genetically affected patients.ResultsGGC repeat expansion was observed in 4 patients (numbers of repeats 44, 54, 96, and 143), accounting for ≈0.73% (4 of 545) of all patients with ALS. A comparison with 1,305 healthy controls revealed that GGC repeat expansion in NOTCH2NLC was associated with ALS (Fisher exact test, 4 of 545 vs 0 of 1,305, p = 0.007). Compared to patients with the neuronal intranuclear inclusion disease (NIID) muscle weakness–dominant subtype, patients with ALS phenotype carrying the abnormal repeat expansion tended to have a severe phenotype and rapid deterioration.ConclusionOur results suggest that ALS is a specific phenotype of NIID or that GGC expansion in NOTCH2NLC is a factor that modifies ALS. These findings may help clarify the pathogenic mechanism of ALS and may expand the known clinical spectrum of NIID.

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