![]() ![]() Piotrkiewicz M, Hausmanowa-Petrusewicz I. ALS-dying forward, backward or outward? Nat Rev Neurol. Amyotrophic lateral sclerosis (ALS): a phylogenetic disease of the corticomotoneuron? Muscle Nerve. The dying forward hypothesis of ALS: tracing its history. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. 2011 43:470–7.įischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, et al. The “dying-back” phenomenon of motor neurons in ALS. Amyotrophic lateral sclerosis: lower motor neuron disease spreading to upper motor neurons. The cortical “upper motoneuron” in health and disease. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, et al. Amyotrophic lateral sclerosis: pathogenesis. Degeneration of Betz cells in motor neuron disease. Apical dendrite degeneration, a novel cellular pathology for Betz cells in ALS. Genc B, Jara JH, Lagrimas AK, Pytel P, Roos RP, Mesulam MM, et al. Progressive spastic paraparesis: hereditary spastic paraplegia and its relation to primary and amyotrophic lateral sclerosis. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Exciting complexity: the role of motor circuit elements in ALS pathophysiology. The human motor cortex microcircuit: insights for neurodegenerative disease. McColgan P, Joubert J, Tabrizi SJ, Rees G. Cortical circuit dysfunction as a potential driver of amyotrophic lateral sclerosis. 2008 31:195–218.īrunet A, Stuart-Lopez G, Burg T, Scekic-Zahirovic J, Rouaux C. Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: implications in health and disease. Jara JH, Genc B, Klessner JL, Ozdinler PH. Pathophysiological and diagnostic implications of cortical dysfunction in ALS. ![]() Geevasinga N, Menon P, Ozdinler PH, Kiernan MC, Vucic S. ![]() Diseased CSMN retained their neuronal integrity and cytoarchitectural stability in two different mouse models that represent two distinct causes of neurodegeneration in ALS. In addition, when UCHL1 gene was delivered selectively to CSMN that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology via AAV-mediated retrograde transduction, the disease causing misfolded SOD1 and mutant human TDP-43 were reduced in hSOD1 G93A and prpTDP-43 A315T models, respectively. However, restoring UCHL1 specifically in CSMN of UCHL1 −/− mice via directed gene delivery was sufficient to improve CSMN integrity to the healthy control levels. When UCHL1 activity is ablated only from spinal motor neurons, CSMN remained intact. Corticospinal motor neurons (CSMN, a.k.a UMNs in mice) show early, selective, and profound degeneration in Uchl1 nm3419 (UCHL1 −/−) mice, which lack all UCHL1 function. UCHL1 (ubiquitin C-terminal hydrolase-L1) is a deubiquitinating enzyme crucial for maintaining free ubiquitin levels. Here, we show UMN loss occurs independent of spinal motor neuron degeneration and that UMNs are indeed effective cellular targets for gene therapy, which offers a potential solution especially for UMN disease patients. There are no effective cures for upper motor neuron (UMN) diseases, such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and hereditary spastic paraplegia. ![]()
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