Selective Expression of Osteopontin in ALS-resistant Motor Neurons is a Critical Determinant of Late Phase Neurodegeneration Mediated by Matrix Metalloproteinase-9

Abstract

Differential vulnerability among motor neuron (MN) subtypes is a fundamental feature of amyotrophic lateral sclerosis (ALS):Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs) and skeletal muscle denervation and atrophy. However, strong evidence suggests the MN pools involved in eye movement and pelvic sphincter control are largely spared in ALS 1,2 . Moreover, within a given MN pool, differences in vulnerability between MN subtypes (e.g. alpha/gamma or fast/ slow) are a fundamental but unexplained feature of ALS. α -MNs are divided into three subtypes: fast-twitch fatigable (FF), fast-twitch fatigue-resistant (FR) and slow-twitch fatigue-resistant (S). The large-diameter low-excitability FF MNs innervate type IIB muscle fibers and degenerate early in the ALS disease course, while medium-excitability FR MNs innervating type IIA muscle fibers follow after that. The high-excitability S MNs innervating type I muscle fibers are largely resistant to degeneration and are preserved, even late in the disease course. Although molecular markers for MNs have been available for several years [3][4][5][6] , the absence of markers that distinguish FF from FR MNs has hindered analysis of the early selective degeneration of MN subtypes.

The vulnerability of spinal motoneurons and soma size plasticity in a mouse model of amyotrophic lateral sclerosis

“…; Morisaki et al . ) motoneurons, respectively. This allowed us to identify soma size ranges for S and FF type motoneurons.…”

Immunochemical characterization on pathological oligomers of mutant Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis

“…This was not described by the changes in total amounts of soluble SOD1 in the lumbar spinal cord, which was actually increased during aging ([14]; also see below). We previously showed that the number of the ChAT-positive motor neurons at 140 days of age was reduced down to one third of those at 60 days of age in G1H mice [24]. The reduced immunostaining with anti-SOD1 olig antibody might thus indicate loss of motor neurons at the disease end-stage.…”

“…2 and 6a). While such decline will be partly because of the concomitant loss of motor neurons [24], mutant SOD1 is also known to accumulate as amyloid-like aggregates in the spinal cord of the model mice after the appearance of motor symptoms [9, 15]. Given that our anti-SOD1 int antibody was not able to react with the amyloid-like SOD1 aggregates in vitro (Fig.…”

Osteopontin and clusterin levels in type 2 diabetes mellitus: differential association with peripheral autonomic nerve function

“…The results of the current investigation suggest an association between OPN and sudomotor dysfunction. The mechanism is, however, unclear as OPN, a widely expressed pleiotropic protein, functions in a number of physiological and pathologic conditions [20]. For example, OPN is involved in bone remodeling, wound healing, vascularization, response to ischemia, and inflammation [20, 21].…”

“…The mechanism is, however, unclear as OPN, a widely expressed pleiotropic protein, functions in a number of physiological and pathologic conditions [20]. For example, OPN is involved in bone remodeling, wound healing, vascularization, response to ischemia, and inflammation [20, 21]. In rodents, OPN was upregulated in denervated motor pathways [1].…”