Selective Vulnerability of Neuronal Subtypes in ALS: A Fertile Ground for the Identification of Therapeutic Targets

Abstract

It is well defined that subpopulations of motoneurons have different vulnerability to the pathology causing amyotrophic lateral sclerosis (ALS). In the spinal cord, the fast fatigable motoneurons have been shown to be the first to degenerate, followed by fatigue-resistant and slow motoneurons. In contrast motoneurons located in the Onuf's and oculomotor nuclei appear to be resistant to disease. With a focus on research mainly done on mice overexpressing the mutated human superoxide dismutase (SOD1) protein, we review recent studies exploring the mechanisms that underlie the selective vulnerability of the various motoneuron subtypes. By comparing differences in gene expression between these populations, it has been possible to identify factors, which critically determine the survival of motoneurons and the neuromuscular function in the pathologic context of ALS. Furthermore, we discuss the contribution of non-cell autonomous processes, involving glial cells and the skeletal muscle, in the neurodegenerative process. Exploring the cause of neurodegeneration from the angle of the selective neuronal vulnerability has recently led to the identification of novel targets, which open opportunities for therapeutic intervention against ALS.

The Timing and Extent of Motor Neuron Vulnerability in ALS Correlates with Accumulation of Misfolded SOD1 Protein in the Cortex and in the Spinal Cord

“…However, even though the mutant SOD1 gene is expressed in all cells and neurons, it was not clear why motor neurons display primary vulnerability. Even though the differential vulnerability of different subtypes of SMN to degeneration in motor neuron diseases is well established [1][2][3][4][5][6][7], the molecular mechanisms underlying the basis of selective vulnerability is beginning to emerge. Therefore, being able to detect misfolded proteins gain attention.…”

“…The misfolded SOD1 was not detected in the spinal cord of WT-eGFP mice (Figure 4a), but low levels of expression became present as early as P30 in the spinal cord of hSOD1 G93A -UeGFP mice (Figure 4b). As the disease progressed with age, the intensity of misfolded SOD1 expression increased mainly in the large size SMN, which among all other SMN, become vulnerable very early and display the fastest rate of degeneration [1][2][3][4][5][6][7]. In contrast, the eGFP+ SMN in the hSOD1 G93A -UeGFP mice, which are degeneration resistant, were devoid of misfolded SOD1 at P30 (Figure 4b), P60 (Figure 4c), P90 (Figure 4d), and even at P140 (Figure 4e).…”

“…However, not all motor neurons are vulnerable to degeneration to the same extent in ALS. For example, large fast fatigable (FF) alpha spinal motor neurons (SMN) are the most vulnerable and the small slow-twitch fatigue-resistant (S) alpha SMN and gamma SMN that innervate the intrafusal fibers are more resistant to degeneration [1][2][3][4][5][6][7]. Likewise, not all corticospinal motor neurons (CSMN) degenerate to the same extent even at the end-stage.…”

“…Misfolded proteins are a hallmark of neurodegenerative diseases [8,9] including ALS [10,11]. Toxic gain of function of mutated misfolded SOD1 protein has been one of the most-widely studied underlying causes of ALS [7], but even today we do not know why different motor neuron pools display a wide range of degeneration in disease. Understanding the basis of selective vulnerability even within motor neuron pools would be instrumental for building treatment strategies.…”

The Dual Nature of Onuf’s Nucleus: Neuroanatomical Features and Peculiarities, in Health and Disease

“…Consequently, muscle denervation occurs early on type IIb muscle fibers, mainly innervated by FF MNs, followed by a second wave of denervation affecting the type IIa muscles, due to the degeneration of fatigue-resistant MNs (Frey et al, 2000 ; Kaplan et al, 2014 ). Instead, the slow MNs are resistant almost until the disease end-stage, still providing the innervation of type I fibers (Rochat et al, 2016 ). Muscles innervated by Onuf’s MNs might result in more resistance to denervation due to the higher percentage of small type I muscle fibers, compared to other skeletal muscles; the presence of slow MNs in Onuf’s nucleus could partially explain Onuf’s neuron resilience in some neurodegenerative diseases.…”