The neurobiology of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis is a degenerative disease affecting the motor neurons. In spite of our growing insights into its biology, it remains a lethal condition. The identification of the cause of several of the familial forms of ALS allowed generation of models to study this disease both in vitro and in vivo. Here, we summarize what is known about the pathogenic mechanisms of ALS induced by hereditary mutations, and attempt to identify the relevance of these findings for understanding the pathogenic mechanisms of the sporadic form of this disease.

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

“…Consistent with this idea, it has been shown that mutations in transport-related genes can result in neurodegenerative phenotypes in mice and humans (3,4). Because transport deficits have been reported in many neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS) (5)(6)(7)(8), it is commonly assumed that disturbances in axonal transport are key pathological events that contribute to neurodegeneration (9)(10)(11). However, the causal relationship of axonal transport disturbances to degeneration remains unclear.…”

Expression of the ALS-Causing Variant hSOD1G93A Leads to an Impaired Integrity and Altered Regulation of Claudin-5 Expression in an in Vitro Blood–Spinal Cord Barrier Model

“…4 Numerous hypotheses for the pathogenesis of ALS have been proposed, which include glutamate toxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, and glial involvement. 5,6 Recently, it was postulated that ALS is a neurovascular disease and that the impairment of the bloodspinal cord barrier is one of the first pathologic events. 7 The blood-spinal cord barrier separates the circulating blood from the spinal cord parenchyma and comprises endothelial cells, astrocytes, and pericytes.…”

The Neurotoxic Tau45-230 Fragment Accumulates in Upper and Lower Motor Neurons in Amyotrophic Lateral Sclerosis Subjects

“…This disease is characterized by the selective death of motor neurons in the brain (upper motor neurons) and spinal cord (lower motor neurons), resulting in the paralysis of voluntary muscles (2)(3)(4)(5)(6)(7)(8)(9). Gene defects are detected in ~5-10% of ALS patients (familial ALS).…”