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

Cylia Rochat, Nathalie Bernard-Marissal and Bernard L. Schneider

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63703

#### **Abstract**

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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 differen‐ ces in gene expression between these populations, it has been possible to identify factors, which critically determine the survival of motoneurons and the neuromuscu‐ lar function in the pathologic context of ALS. Furthermore, we discuss the contribu‐ tion 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.

**Keywords:** motoneurons, SOD1, selective vulnerability, therapeutic target, ER stress

#### **1. Introduction**

Amyotrophic lateral sclerosis (ALS) primarily affects the motor system, which controls both voluntary and involuntary movements, including vital functions such as breathing, through

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the activity of various types of motoneurons (MNs). Paralysis and death of the patients, which typically occurs within a few years after disease onset, is caused by the progressive dysfunc‐ tion and degeneration of MNs in the cortex, brainstem and spinal cord. Remarkably, it has been established that the different types of MNs are not equally affected by ALS. This leads to contrasted effects on the motor system. For instance, with disease progression, patients lose their ability to speak, swallow and move, but they keep normal visual, sexual and bladder functions. Indeed, MNs located in the oculomotor and Onuf's nuclei are remarkably resist‐ ant to the disease [1]. In contrast, spinal MNs controlling voluntary movements, hypoglossal MNs important for swallowing and breathing, as well as the upper MNs, are typically among the first neurons to degenerate.

Upper MNs, also known as Betz cells or corticospinal MNs (CSMNs), are glutamatergic neurons located in the primary motor cortex and which activate lower MNs in the brainstem and spinal cord. Upon activation, the lower MNs induce muscle contraction via the release of the acetylcholine neurotransmitter in the neuromuscular junction (NMJ), a specialized synapse contacting the skeletal muscle fibers. The ensemble formed by lower MNs and the innervated muscle fiber is called the motor unit.

Spinal MNs are subdivided into α, β and γ MNs, depending on the type of muscle fibers they innervate (reviewed by [2]). In ALS, it is mainly α-MNs that degenerate. However, it is recognized that within the class of α-MNs, there is also a predictable variation in neuronal vulnerability to disease [3, 4]. It is therefore important to distinguish the following sub‐ types of α-MNs, defined by the contractile properties of the motor unit they are part of: the fast twitch fatigable (FF) MNs, the fast twitch fatigue-resistant (FR) MNs and the slow twitch fatigue-resistant (S) MNs [5]. This classification is also based on other characteristics, such as the size of the neuronal soma (FF MNs have larger cell bodies than S MNs), axonal conduc‐ tion velocity (FF MNs are faster than S MNs), dendrite branching (FF MNs display a more complex dendritic tree than S MNs) [6], as well as the electrical properties of each of these MN subtypes [7].

The selective vulnerability observed between the different types of MNs provides a remarkable opportunity to explore the factors that specifically contribute to neurodegeneration. Until now, this approach has been mainly based on animal models overexpressing mutated forms of the superoxide dismutase 1 (SOD1) protein. Indeed, in more than 20% of the familial ALS cases (fALS), the SOD1 protein carries point mutations associated with autosomal dominant inheritance. Rodent models overexpressing mutated forms of SOD1 (mSOD1), often under the control of the human SOD1 promoter, faithfully replicate major clinical aspects of ALS [8–10]. Furthermore, MN subpopulations display a selective vulnerability pattern very similar to the one observed in humans [8]. These animal models are therefore instrumental to investigate the molecular and cellular mechanisms underlying the disease process. In this review, we will discuss how the research on ALS has identified novel therapeutic targets by comparing different MN subtypes in SOD1 models of fALS.
