Neuroprotection through Excitability and mTOR Required in ALS Motoneurons to Delay Disease and Extend Survival

Abstract

Delaying clinical disease onset would greatly reduce neurodegenerative disease burden, but the mechanisms influencing early preclinical progression are poorly understood. Here, we show that in mouse models of familial motoneuron (MN) disease, SOD1 mutants specifically render vulnerable MNs dependent on endogenous neuroprotection signaling involving excitability and mammalian target of rapamycin (mTOR). The most vulnerable low-excitability FF MNs already exhibited evidence of pathology and endogenous neuroprotection recruitment early postnatally. Enhancing MN excitability promoted MN neuroprotection and reversed misfolded SOD1 (misfSOD1) accumulation and MN pathology, whereas reducing MN excitability augmented misfSOD1 accumulation and accelerated disease. Inhibiting metabotropic cholinergic signaling onto MNs reduced ER stress, but enhanced misfSOD1 accumulation and prevented mTOR activation in alpha-MNs. Modulating excitability and/or alpha-MN mTOR activity had comparable effects on the progression rates of motor dysfunction, denervation, and death. Therefore, excitability and mTOR are key endogenous neuroprotection mechanisms in motoneurons to counteract clinically important disease progression in ALS.

Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis

“…Rapamycin-induced autophagy not only reduced the accumulation of FUS-positive stress granules, but also prevented fragmentation of neurites and neurotoxicity in cultured cortical neurons ectopically expressing ALS-linked FUS(R521C) [91]. In comparison, rapamycin failed to exhibit a beneficial effect on motor neuron survival in other ALS model mice expressing pathological mutants of either SOD1 or VCP [92][93][94][95]. Moreover, chronic treatment of rapamycin results in more severe impairment in mitochondrial integrity, higher levels of pro-apoptotic Bax, and caspase-3 activation in spinal motor neurons in SOD1(G93A) mice, all of which may contribute to demise of motor neurons [92].…”

The phenotypic variability of amyotrophic lateral sclerosis

“…The size of the motor neurons, the length of their axons, their metabolic rate and many other characteristics have been hypothesized as contributors, but never proven to have a role. Some evidence suggests that the low abundance of calcium buffering proteins 104 and the presence of mitochondrial matrix metalloproteinase-9 105 underlie the difference in vulnerability between oculomotor and other motor neurons.Expression of the ephrin type-A receptor 4 protein (encoded by EPHA4), 106 as well as excitability characteristics, 107 have been suggested to contribute to the difference in vulnerability of large versus small motor neurons. Susceptibility of motor neurons to excito toxi city could explain why spinal sensory neurons are less vulnerable to ALS than are motor neurons.…”

“…108 Moreover, studies in SOD1 mutant mice suggest that the vulnerability of motor neurons is related to specific excitability-related pathways in these cells. 107 Polymorphisms in the UNC13A gene and expression levels of EPHA4 have been suggested to contribute to the variability in disease severity. 106,109 ATXN2 expansions are a risk factor for ALS but not for FTD, 90 whereas the TMEM106B risk allele is a risk factor for FTD but not for ALS.…”

Mutant SOD1 protein increases Nav1.3 channel excitability

“…The mechanisms whereby neurons in ALS may become hyperexcitable are multiple, with data implicating both endogenous membrane changes as well as excessively excitatory synaptic inputs [10,42,43] and excitatory stimuli from an astrocyte conditioned medium [9]. However, as indicated above, recent data have raised the important possibility that early motor neuronal hypoexcitability may be pivotal in ALS and other neurodegenerative disorders, initiating a cascade of events that compromise neuronal viability with hyperexcitability as a compensatory rather than a primary phenomenon [13,14]. Resolution of these two viewpoints will await further studies, although we note that the observation that mutant SOD1 directly augments sodium channel excitability is consistent with a primary, upstream role for hyperexcitability in neuronal pathology in ALS.…”

“…The hyperexcitability reflects at least three factors: intrinsic hyperexcitability of the neurons themselves, excessive excitatory inputs from interneurons [10], and pro-excitatory effects of soluble factors secreted by astrocytes [9]. Hypoexcitability has also been observed in iPSC-derived ALS motor neurons [12] and is also proposed to be a critical element in the early vulnerability of selected neuronal populations in ALS [13,14].…”