AMYOTROPHIC LATERAL SCLEROSIS: RAPIDLY ACCELERATING COMPLEX NEURO-DEGENERATIVE DISEASE

AMYOTROPHIC LATERAL SCLEROSIS: RAPIDLY ACCELERATING COMPLEX NEURO-DEGENERATIVE DISEASE  

Ashwani Arya ^{* 1}, Priya Tyagi ¹, Shweta Yadav ² and Renu Kadian ³

Department of Pharmaceutical Education and Research ¹, BPS Women University, South Campus, Bhainswal Kalan, Sonepat - 131305, Haryana, India.

Department of Pharmacy ², Faculty of Pharmaceutical Sciences, PDM University, Bahadurgarh - 124507, Haryana, India.

Ram Gopal College of Pharmacy ³, Farrukhnagar, Gurugram - 122506, Haryana, India.

ABSTRACT: An amyotrophic lateral sclerosis is a group of progressive neurodegenerative disorders of motor neurons that leads to weakness, muscle atrophy, progressive paralysis, and respiratory insufficiency with a life anticipation of only three years after the onset of disease symptoms. It impairs the functions of both upper and lower motor neurons. The specific mechanism for the disease remains largely unidentified. At present, there is no specific treatment to cure or reverse the progression of the disease. ALS is generally diagnosed based upon the medical history and signs and symptoms; however, it is quite difficult to diagnose the disease in its initial stages. Several studies indicate that various predominant disease mechanisms such as oxidative stress, excitotoxicity, mitochondria dysfunction, aberrant protein homeostasis, defective RNA processing, formation of cytoplasmic inclusion, endoplasmic reticulum stress, endosomal dynamic dysfunctions, protein aggregation, neuroinflammation, oligodendrocyte degeneration, and microglial activation are involved in the pathophysiology of ALS. The various gene mutations (c9orf72, TARDBP, SOD1, and FUS) are also associated with disease mechanisms, so ALS is a complex genetic disorder involving multiple combinations of genes in amalgamation with environmental exposures. Through targeting the above-said disease, mechanisms is likely to contribute to the development of novel therapeutic treatments for the patients suffering from ALS. The review papers present the overview of key disease mechanisms and associated gene mutations involved in the pathophysiology of ALS, its clinical features, and several brain regions involved in the disease.

ALS, Genes, Oxidative stress, Excitotoxicity, Mitochondria

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly accelerating complex adult neurodegenerative disease that impaired the functions of upper motor neuron (UMN) and lower motor neurons (LMN) that results in motor paralysis and muscle atrophy ^1-3.

The fatality of disease (usually within 3-5 years) is characterized by an escalating and unsymmetrical weakness and atrophy of muscles (limb, thoracic, abdominal, and bulbar muscles) ^4-5. The disease starts with dysarthria and dysphagia, leading to breathing difficulty, resulting in the weakness of respiratory muscles, and the death is due to respiratory failure in the final stage of ALS. There is no such treatment available for the disease except one medication known as riluzole which can cure or reverse the main symptoms of the disease completely ⁶. As compared to the females, the disease incidences are higher in males to some extent, with about a 1.5:1 ratio.

The individuals of age group 55 to 75 years are more affected by this disease ⁷. In the brain and spinal cord, the nerve cell of motor neurons gets stuck and dies. This phenomenon impaired the motor neurons functioning that ultimately impaired muscle movement control in the brain and spinal cord, which leads to loss of muscle mass, weakness of muscle, and inability to control the movements of the body. The gradual decline in strength leads to paralysis and loss of muscle functions ^{1, 7}.

ALS impaired the functions of UMN such as spasticity, slowness of movements, poor balance, and in coordination, which is present in the brain and also impaired the functions of LMN (muscle weakness, muscle atrophy, twitching, or fasci-culation’s), which are present in the spinal cord and brainstem stem⁸. Several studies indicate that various gene mutations such as c9orf72, TARDBP, SOD1, FUS are associated with the disease mechanisms such as like glutamate excitotoxicity, damage of mitochondria, aggregation of the protein, dysfunction of microglia, neuroinflammation, aberrant RNA metabolism, defective DNA metabolism, and defective transport of axon involved in ALS. These are all pathological mechanisms that probably play a role in motor neuron degeneration in ALS ^{2, 9, 10}.

However, major barriers to the development of effective therapeutic strategies in ALS are due to the poor understanding of the pathophysiology of ALS. It also affects all the functions and integrity of brain networks ^11-13. ALS is a multifactorial and multisystem composite disease of the neurons. The various mechanisms entail the pathogenesis of this disease. All the above factors result in the functional loss of the specific body part and causing its paralysis due to impairment of neurons. Through targeting these pathogenic factors, there is a possibility to detect the superior biomarkers and also to enhance the therapeutic approach towards the remedies of ALS ^{4-5, 12}. This review paper gives a novel understanding of the predominant factors involved in the disease mechanism with associated genes and various brain regions impaired in ALS.

Symptoms of ALS: The prime manifestations of ALS can fluctuate among patients; some may be having a spinal - onset disease (i.e., the outbreak of the muscle fragility of the limbs). The other patients may have a bulbar-onset disease that is represented by dysarthria and dysphagia. The cause of ALS is undetermined in most patients, whilst some patients with familial disease are accompanied with genetic mutations that have a broad spectrum of functions, even in non-motor cells. Almost 50% of victims are prone to cognitive and/or behavioural impairment during the disease course. Dysphagia, muscle weakness, spasticity, concomitant behavioural variant frontotemporal dementia (FTD) is identified in 13% of patients as initial symptoms of ALS ^{14, 15}. Fasciculation cramps, muscle atrophy and marked weakness, are the manifestations of LMN’s degeneration and loss which includes spasticity, hyperreflexia, and modest weakness is due to impairment of UMN’s.  Language, judgment, personality trait is affected, and the executive functions get altered. The Decision-making capability of patients with ALS and dementia also gets affected for a short duration of time ¹⁶.

Emotional symptoms if present, can lead to poor appetite and impairment in sleep quality of life. Degeneration of sensory neurons can occasionally lead to pain and extreme suffering. Pain frequently resulted from contractures, inability to turn in bed and loss of mobility. The primary respiratory manifestations include weakened cough, dyspnoea, morning headache and orthopnoea ¹⁷. Patients may experience depression and anxiety at some stage during respiratory failure.  The manifestations of motor neuron disorder typically initiate with focal weakness in one limb. During disease, distal muscles are affected most often, and patients may experience hand clumsiness or foot drop. Head drop is observed when the neck extensor muscles are affected. Upper motor neuron participation may result in muscle cramps and rigidity. In 20% of patients, the manifestations are first observed in the bulbar muscles causing dysarthria and dysphagia ^{4, 18, 19}. The various clinical signs and symptoms are presented in Fig. 1.

Classification of ALS: Motor neuron disorders (MND) is a type of neurodegenerative disease, which leads to significant disability and death throughout the impaired motor system. HSP, SMA, and ALS are the types of MND and HSP is pure LMN type, and SMA is pure UMN type. ALS is a common type of motor neuron disorder. ALS can be systematized into two major categories: sporadic (idiopathic) and familial. Familial ALS occurrence depends on a dominant trait and affects about 5% to 10% of patients with ALS ^{20, 21}.

Approximately 67% males are influenced by sporadic ALS and it encompasses all other patients with ALS ¹. Familial ALS showed an ailment male to female ratio of 1:1.1 Patients with ALS in early childhood and late teens are more prone to familial ALS, whereas the probability of being infected by sporadic ALS is higher in usually in their mid-to-late fifties. Immune system abnormalities, glutamate toxicity, mitochondrial dysfunctions may be possible causes of ALS ²².

There are four main presentations of ALS are Primary lateral sclerosis (PLS) with pure UMN participation, limb-onset ALS (UMN and LMN type), progressive muscular atrophy (pure LMN implication), bulbar-onset ALS (associated with dysarthria and dysphagia) and as the disease progresses limb features abnormalities occurs. PLS implicates deterioration of the LMN type, and it is associated with speech impairments, spastic tetraparesis, and urinary urgency ^22-24. The manifestations of PLS include the successive amelioration of severe muscle spasticity and rigidity and prudent muscle atrophy ¹⁴. The prime consideration of PLS being diagnosed as ALS requires confirmation of LMN malfunctioning of at least one limb or region, and in the majority of patients, it ended as ALS. At least two body regions are involved in the interpretation of ALS being diagnosed as limb-onset ALS. Relevant genetic testing should be done in the examination of progressive muscle atrophy (PMA), which can only be confirmed as ALS if altered at least two body regions that cancel out the possibility of other motor neuron disease ²². The major types of motor neuron disorders and specified features with their clinical phenotypes are presented in Fig. 2 ^{12, 15, 25-28}.

FIG. 1: CLINICAL FEATURES OF ALS

FIG. 2: VARIOUS TYPES OF MOTOR NEURON DISORDERS. PD: progressive degeneration; LMN: lower motor neurons; AH: anterior horn. SC: spinal cord PS: progressive spastkity; UMN: upper motor neurons: MNDs: Motor neuron disorders; SMA: Spinal muscular atrophy; ALS: amyotrophic ateral sclerosis; HSP: hereditary spastic paraplegia; PLS: Primary lateral sclerosis; PMA Progressive muscula atrophy; FLDS: ALS-frontal lobe dementia syndrome ; FTLD: frontotemceal lobar degeneration ; Mk Muscle atrophy): Paralysis; IL: Lower Limb

Pathophysiology of ALS: The oxidative stress, axon dysfunction (transport and retraction), mitochondria dysfunction, aberrant protein homeostasis, defective RNA processing and formation of cytoplasmic inclusion, protein aggregation, neuroinflammation excitotoxicity, oligodendrocyte degeneration, and microglia activation are the various factors involved in the pathophysiology of ALS ^9-14. The impaired protein homeostasis, aberrant RNA metabolism is the chief element linked to multiple genes in ALS which leads to neuronal injury. The mutation in CHCHD10 gene can lead to mitochondrial dysfunction and protein aggregates which give rise to the deficiency of respiratory chain under the influence of others causing ALS related mutations.  Both factors can cause an increase in the oxidative stress that ultimately affects the system of protein homeostasis. The dysfunction of astrocytes EAAT2 leads to impaired glutamate excitotoxicity, which further causes mitochondrial dysfunction.

The proinflammatory cytokines and reactive oxygen species secrete from the activated microglia M1 cause the inflammation. Glutamate-induced excitotoxicity is involved in the pathophysiology of ALS. Neurodegeneration is caused by the generation of free radicals, which leads to impairment in the proinflammatory mediators and intracellular organelles ^{17, 20-24, 26-29}. The common pathophysiology mechanism cascade involved in ALS is summarized in Fig. 3.

Motor neuron degeneration results in over-activation of glutaminergic receptors present in the post-synaptic neuron, and the postsynaptic glutamate receptor activation may ascribe to reduced uptake of glutamate by astrocytic processes. This leads to an influx of considerable Ca²⁺ through ionotropic receptors and enhancing intracellular Ca²⁺ levels that result in activation of digestive enzymes (proteases, nitric oxide synthase and phospholipase-A₂. Augmentation in intracellular Ca²⁺ leads to depletion of mitochondrial function, causing generation of free radicals, depletion of adenosine triphosphate formation and combined with ATP production impairment, nitric oxide etc., leads to Na⁺/K⁺ pump inactivation, enhancing intra-cellular Na⁺ concentrations, causing depolarization of neurons.  As a repercussion, Na⁺/Ca²⁺ exchange may work reversely to endeavor normal intra-cellular Na⁺ concentration, but due to influx of Ca²⁺ may augment the previously raised intra-cellular Ca²⁺ concentration. Excitotoxicity may lead to degradation of axonal transport. Moreover, the production of aggregates in the cytoplasm (TDP-43, SOD-1, and FUS gene mutations) caused neurodegeneration by unspecified disease mechanisms. Microglia intrusion indicates the progression of neuroinflammatory processes that may intensify excitotoxicity by inflammatory cytokine generation ^29-33. Rothstein et al., found elevated levels of glutamate in the cerebrospinal fluids of patients suffering from ALS. It was concluded from the study that glutamate, which mediates excitotoxicity, plays a key role in the degeneration of motor neurons ³⁰. Extreme glutamate levels stimulate the AMPA and NMDA presynaptic glutaminergic receptors, which leads to the excitotoxicity through the increase the Ca²⁺ ions, enter the cell ^30-33. Increased Ca²⁺ influx level in cells activates enzymes like phospho-lipases, endonuclease, and cabin as protease. These processes lead to the injury of the neurons and death of cell ³¹.  Rothstein et al., accounted for the deficit of particular EAAT2 glutamate transport in ALS patients ²⁹. The atypical splicing of EAAT2 mRNA due to deficit of EAAT2 in affected areas of CNS causes the increased glutamate synapses extent ²⁶. ALS pathogenesis is associated with glutamate-induced excitotoxicity ³³. Generation of free radicals is a consequence of glutamate-induced excitotoxicity, which results in damaging intra-cellular organelles and up-regulating pro-inflammatory mediators, thus causing neurodege-neration ^{34, 35}. In relation to glutamate-induced excitotoxicity, structural mitochondrial defects, Na⁺/K⁺ ion pump dysfunction, altered the system of axonal transport, and autophagy are involved in ALS pathogenesis ^36-39.

Mitochondria play a major role in the regulation of cellular metabolism, Ca²⁺ signaling, calcium homeostasis, maintenance of membrane potential, and production of ATP ⁴⁰. Impaired intracellular signals such as membrane potential, Ca²⁺ homeo-stasis, bioenergetic and myophagy cause the neuronal death and ultimately lead to mitochondria dysfunction. Several defects in function as well as the structure of mitochondria, such as lack of respiratory control, reduced membrane potential, decreased consumption of oxygen and impaired respiratory functions found in mitochondria of astrocytes of genetically mutated SOD1-G93A rats ⁴¹. Astrocytes and microglia directly caused neurodegeneration by various processes (inadequate release of neurotoxic mediators, neurotrophic factors and glutaminergic receptor modulation). Progressive neurotoxicity caused by microglia dysregulation and its over activation ^{42, 43}.

Axonal transport is accountable for the transport process of various cell organelles, proteins, mitochondria, and lipids in between the neuron cell bodies and axonal cytoplasm. In ALS, the dysfunction of occasional functions and accumulation of organelles in the cell body and other proteins are the main factors which contribute to the pathogenesis of disease. The main cytoskeleton protein in the motor neurons is neurofilament (NFs) and they play a major role in maintaining structural support to the axon, axonal growth and regulating axonal diameter. The unusual accumulation of NFs in the cytoplasm responsible for the motor neurons degeneration and overexpression of the NFs cause the occasional atrophy, dysfunction of motor neurons and peripheral accumulation of NFs⁴⁴. Oxidative stress plays a major part in neurodegenerative disorders. Oxidative stress damages the DNA, lipids and proteins in the tissue of the CNS of transgenic mouse models of FAS expressing SOD1 ³⁵.

The primary cause of disability among patients is muscle weakness. The spinal muscular atrophy, the other age-related cachexia and spinal bulbar muscular atrophy are the major contributors of muscle weakness. Several studies indicate that neurobiological changes in brain regions such as the motor cortex, corpus callosum, sensorimotor, premotor, prefrontal, thalamic regions, anterior temporal cortices etc. implicated in ALS, which impaired the cognitive levels, atrophy, compen-satory cortical plasticity, neuronal loss, degeneration, decrease executive functions.

The GABA, serotonin, astrocytes, and activated microglia associated with the brain regions implicated in the ALS ^44-54. The various brain regions affected in ALS which affect the cognitive domains are summarized in Fig. 4 ^{11, 44-54}.

The neurodegeneration mechanisms underlying ALS are multifactorial and interrelated molecular and genetic pathways. Distinctly, neurodege-neration in ALS may be an outcome of complicated interlinks age of various disease mechanisms associated with mutations of several genes. A majority of gene mutations such C9orf72, SOD1, TARDBP and FUS are recognized to be linked with the disease mechanism of ALS. The various factors involved in the pathophysiology disease mechanism of ALS are summarized in Table 1, and the various genes associated with the disease mechanism in ALS are summarized in Table 2.

Several disease mechanisms associated with several gene mutations play a major role in the pathophysiological mechanism of ALS. Through targeting the predominant factors in disease mechanism with associated gene mutations, can be base for therapeutic remedies of ALS and play a key role in the development of better management of this complex neurodegenerative disease.

FIG. 3: PATHOPHYSIOLOGY MECHANISM IMPLICATED IN ALS

FIG. 4: THE COGNITIVE DOMAINS TYPICALLV AFFECTED IN THE ALS PMC. Prirrery Motor cortex; CC Cerebral Cortex; WMF: Whitte mater fibres; EMA: Extra Motor Area; NAA: N-acetyl as partate; PSC Primary sensory cortex; BG: Basal ganglia; SIC: Sensori Motor Cortex; CT: Corticospi nal tract ; LMN: Lower Motor Neuron; GAGA-AR: Gama amino butyric acid -Areceptors; MEI: Mid brain; MTC Medial Temporal Cortex; PC: Pyramidal cells; SMN: Sensori Motor Network ATC: /InteriorTemporal Cortices; T: Temporal; IOC: Inferior Parietal Cortex

TABLE 1: PATHOPHYSIOLOGICAL MECHANISM IMPLICATED IN ALS

VDAC1: Voltage-dependent an ion channel isoform 1; HK1; Hexokinase 1; VCP:  valosin-containing protein; UBQLN2: ubiquilin-2; TER ATPase transitional endoplasmic reticulum ATPase; VAPB: vesicle-associated membrane protein-associated protein B/C; SRSF1: serine/arginine-rich splicing factor 1;  NXF1 : nuclear RNA export factor 1; NEFH : neurofilament heavy poly peptide UNC13A  : protein UNC-13 homologue A;  AMPA : α--amino-3-hydroxy-5-methyl-4- isoxa zolepropionic acid ; NRNA BP nuclear RNA- binding proteins; SETX: senataxin; ELP3: Elongator protein 3; TARDBP: TAR DNA binding protein

TABLE 2: GENES MUTATIONS ASSOCIATED WITH DISEASE MECHANISM IN ALS

SODI: Superoxide Dismutase 1); TARDBP: TAR DNA binding protein; FTD: frontotemporal dementia; TBK1: TANK- binding kinase 1; FUS:  Fused in sarcoma/translated in liposarcoma; TARDBP/ TDP-43: Transactive response (TAR) DNA-binding protein 43 (TARDBP/ TDP-43); f -ALS familial amyotrophic lateral sclerosis; ROS: reactive oxygen species; CHCHD10 (coiled-coil-helix-coiled-coil-helix domain-containing 10

CONCLUSION: ALS is a fatal neurodegenerative disorder in which the functions of lower and motor neurons are impaired. Neuronal dysfunction is the main symptom of neurodegenerative disorder which ultimately leads to the death of cells. The various mutations of genes like c9orf72, TARDBP, SOD1, and FUS and associated with several predominant disease mechanisms such as oxidative stress, axon dysfunction, mitochondria dysfunction, aberrant protein homeostasis, defective RNA processing and formation of cytoplasmic inclusion, endoplasmic reticulum stress endosomal dynamic dysfunctions, protein aggregation, neuroinflam-mation, excitotoxicity, oligodendrocyte degeneration and microglial activation are responsible for the disease. Through the understanding of various disease mechanisms involved in the base of the pathophysiology associated with several gene mutations and brain regions impaired in ALS, a suitable therapeutic approach towards the management of the disease can be obtained through targeting these mechanisms of disease progression.

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: All the authors declare no conflict of interest.

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    Arya A, Tyagi P, Yadav S and Kadian R: Amyotrophic lateral sclerosis: rapidly accelerating complex neurodegenerative disease. Int J Pharm Sci & Res 2021; 12(6): 3078-89. doi: 10.13040/IJPSR.0975-8232.12(6).3078-89.

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