Neurodegeneration refers to the condition which primarily affects neurons [1]. Hippocrates (460-375 BC), in his important treatise entitled ‘On The Sacred Disease’ describes epilepsy and relates it with the brain. In the ancient period, neurological disorders were classified under humor- Vata rogas (diseases) in Ayurveda. Vata refers to the energy present in the body involved in controlling both voluntary and involuntary functions. Any change in vata leads to the pathogenesis of the neurodegenerative disease. In Ayurveda, about eighty types of neurological disorders have been described, such as apasmara /apasmati (Epilepsy), kampavata (Parkinson’s disease). The clinical symptoms and treatments of neurodegenerative disease have been described by Hippocrates [2-5].

The clinical symptoms of neurodegenerative diseases are often characterized by alteration in cognitive function, movement, memory and learning, co-ordination and autonomic control [6]. Worldwide neurological disorders have more than 6% of the total burden of diseases [7]. The most common neurological diseases are Alzheimer's Disease (AD), Parkinson’s Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), fronto-temporal dementia and the spinocerebellar ataxia (Table 1).

Neurodegenerative diseases/disorders have different pathophysiology, along with cognitive impairments. The loss of brain cells in neurodegenerative diseases is not a rapid process but rather a very slow process that becomes worse during the progression of the disease. Sporadic, as well as familial forms of neurodegenerative diseases, are common in the human population. These forms are difficult to distinguish phenotypically as well as histologically. A number of causative genes have been discovered for the neurodegenerative disease [8]. James Parkinson was born on April 11, 1755, in the semi-urban hamlet of Hoxton, Northeast of the city of London, England. He describes PD for the first time. PD is an age-progressive disease, (second after AD), of the nervous system. James Parkinson was the first who provided a description of “Paralysis agitans” or “Shaking palsy”, in his popular monograph named “An Essay on the Shaking Palsy”, in 1817 [9, 10].

PD is a complex neurological disorder of CNS that affects mainly the motor system of the body. The non-motor symptoms also become worsen as the disease progresses [11, 12]. Early symptoms of the PD are shaking, rigidity, slowness of movement, and difficulty in walking [13, 14]. The behavioural problems may also occur with the disability of thinking power. It is reported that about 3% of the affected

people are above 65 years of age [15]. In PD, nerve cells of substantia-nigra of the mid-brain are degenerated. The basal ganglia help in initiating and smoothening of voluntary muscle movements, suppresses involuntary movements and problem in the coordination in changes of posture [16, 17]. Each part of the brain consists of Globus pallidus i.e. internal and external. The other part of the brain which is involved in the neurotransmitter function is the striatum, which includes caudate nucleus, putamen and substantia nigra. There are basically two pathways by which three main neurotransmitters work i.e. Glutamate, GABA and Dopamine [18, 19]. The basal ganglia release neurotransmitters (chemical messenger) for the activation of nerve impulse pathways. The main neurotransmitter in the basal ganglia is dopamine [20]. If the nerve cells in the basal ganglia are degenerated then there will be less production of dopamine, leading to the loss of control on muscle movements (Fig. 1). It leads to tremors, bradykinesia, hypokinesia, posture problems and the loss of overall coordination of functions. The substantia nigra, which is degenerated in PD plays an important role in the normal functioning of motor and non-motor activity of the body. The substantia nigra sends chemical message through axons that pass throughout the striatum and help in the movement of a particular part of the body. This is known as the nigrostriatal pathway or dopamine secretion pathway [21, 22].

The signals from one neuron to another are transferred through the active neuron refers as dopaminergic neurons. Within the striatum, there are neurons having specific receptors to recognize and respond to dopamine only. These receptors cannot be activated by any other neurotransmitters. When the cells in substantia nigra are dead, the level of dopamine decreases rapidly as a result, striatal cells are not activated and the PD symptoms increases day by day [23, 24]. The presence of dopaminergic neurons in the brainstem was first reported by Dahlstrom and Fuxe in 1964. In the pathophysiology of PD, the importance of dopamine depletion was first suggested by Carlsson in the late 1950s [25, 26]. In 1960, Ehringer and Hornykiewicz published their report after examining six cases of PD that the dopamine content in the neostriatum was found to be severely reduced. Dopamine (an amine), is synthesized by a precursor molecule L-Dopa. It is synthesized in the brain as well as in kidneys [27, 28].

It is well established that dopamine itself is a neurotransmitter that is synthesized in substantia nigra and transported to the striatum via the nigrostriatal tract. Several other functions have also been attributed to dopamine i.e. it can act as a vasodilator, it enhances sodium excretion and urine output; it reduces insulin production, gastrointestinal motility and protects intestinal mucosa. It also reduces the activity of lymphocytes [25, 29]. Dopamine is not able to cross the blood-brain barrier, so the interest was focused on the dopamine precursor levodopa. Levodopa takes entry into the brain with a large neutral amino acid transport pathway and can be decarboxylated to form dopamine. Henry Dale, a Physician, was first to examine the biological activity of dopamine in 1910. He suggested the shorter name dopamine in 1952. The Physician George Barger and James Hill synthesized 3,4-dihydroxyphenylethylamine at The Well-Come Laboratories in London [30]. At the same time, Kathleen Montagu and Arvid Carlsson, together with Lindqvist, Magnusson, and Waldeck in 1957, reported the presence of dopamine in the brain, and in 1959, the Swedish group claimed the presence of dopamine in high concentrations in the striatum [31-33]. Marthe Vogt suggests that there is a continuous discharge of dopamine but was not sure about dopamine to be a conventional neurotransmitter in the neurons of nigrostriatal regions [34]. Dahlstrom (1973) [35] was also not sure about the presence of dopamine in the Central Nervous System (CNS). Dopamine receptors play an essential role in daily life functions. There are various dopamine receptors in the CNS, specifically in the hippocampal dentate gyrus and sub-ventricular zone. The five types of dopamine receptors, namely, D1, D2, D3, D4, and D5 has been described to date. Each receptor has a different function. According to Mishra et al. (2018) [36] the functions of various dopamine receptors are as follows:

Further, the two types of sub-families of dopamine receptors are D1-like family and D2 like family. The D1 and D5 receptors belong to D1-like family of dopamine receptors, and D2, D3 and D4 receptors belong to the D2-like family [37]. D1 and D5 receptors coupled to G stimulatory sites and activate adenylyl cyclase. The activation of adenylyl cyclase leads to the production of the second messenger cAMP, which further leads to the production of protein kinase A (PKA) and affects transcription in the nucleus [38, 39]. The D1 receptor is most abundantly distributed in the CNS, followed by D2, D3, D5 and D4 (D1>D2>D3>D5>D4) [40]. D1 receptors regulate the development of neurons are play an important role in the regulation of most of the cognitive activities as well as locomotion [41]. D1 and D5 receptors have high density in the striatum, nucleus accumbens, olfactory bulb, and substantia nigra. D1 and D5 receptors, along with stimulating adenyl cyclase, also activates phospholipase C, which leads to the induction of intracellular calcium release and activation of protein kinase C. Protein kinase C is a calcium-dependent protein kinase. Calcium is also involved in modulating the neurotransmitter released by exocytosis. D1 and D5 inhibits Na/K ATPase i.e. cyclic AMP-dependent Protein Kinase (PKA) calcium- and phospholipid-dependent Protein Kinase (PKC) pathways in the kidneys [42]. D2, D3, and D4 receptors are expressed mainly

in the striatum, external globus pallidus, core of nucleus accumbens, hippocampus, amygdala, and cerebral cortex. These receptor affects the postsynaptic receptor-mediated extrapyramidal activity. D2-D4 receptors are important for signaling, the survival of human dopaminergic neurons and their development [43, 44]. It has been reported in mice that the dysfunction of the dopaminergic pathways leads to neurological and psychiatric disorders [45, 46]. Fig. (2) shows a comparison of the normal brain with a brain affected by various factors that are responsible for inducing PD. The dopamine signaling is important for maintaining the normal physiological processes. The disruption of pathways may lead

to the dysfunctions attributed to neurodegenerative disorders. Tyrosine in the presence of Tyrosine Hydroxylase (TH) is converted into L-Dopa. Then, L-Dopa is converted into the Dopamine in the presence of DOPA Decarboxylase (DDC). Dopamine is transported from the cytosol by a Vesicular Monoamine Transporter (VMAT2) into the synaptic vesicles where it is stored until its release into the synaptic cleft. Dopamine receptors are present in both post as well as pre-synaptic neurons (including Dopamine Transporter, DAT). The required dopamine reaches the postsynaptic synapse through the dendrites, which leads to the normal functioning of both motor and non-motor neurons [47].

Several common cellular mechanisms of protein aggregation are involved in the progression of neurodegenerative diseases. The β-amyloid is the main part of plaques formation in AD, α-synuclein for Lewy bodies (LBs) formation in the substantia nigra in PD and dementia with LBs (DLB), and expanded repetition of polyglutamine is found as intra-nuclear and cytoplasmic inclusions in HD [48, 49]. The LBs were first described by F.H. Lewy in 1912, in the nucleus of Basalis of Meynert and the dorsal vagal nucleus in patients with PD. It was named in the honour of Friederich H. Lewy by Tretiakoff, who confirmed the presence of LBs in the substantia nigra [50-52]. LBs are rounded, eosinophilic and intra-cytoplasmic neuronal inclusion or aggregation of α-synuclein. According to some studies, the LBs are found in the selected areas of the brain i.e. substantia nigra, locus ceruleus, dorsal vagal nucleus, the nucleus of Meynert, hypothalamus cortex and sympathetic ganglia [53-55]. For the last 20 years several important discoveries have been made by researchers on the genetics of PD. The SNCA and its mutations are associated with autosomal dominant parkinsonism [56, 57]. Mutations in this gene include missense, which results in amino acid substitutions. SNCA-related PD is not so common, but identification of SNCA mutations has led to the identification of α-synuclein as the major component of Lewy bodies [58-61]. α-synuclein has 140 amino acids, that belongs to the family of related synucleins (β-synuclein of 134 amino acids) [62, 63]. α-synuclein contains an acidic stretch towards the C-terminus and there are no cysteines and tryptophans. Structurally, human α-synuclein consists of three regions i.e. an N-terminal amphipathic region, a hydrophobic central region, and an acidic C-terminal region [61, 64-66]. Six genes have been found to be associated with autosomal dominant forms of PD i.e. SNCA, LRRK2, VPS35, EIF4G1, DNAJC13, and CHCHD2 and three with autosomal recessive forms of PD i.e. Parkin, PINK 1 and DJ-1 [67, 68].

Three genes (parkin, PINK1 and DJ1) have been identified to be associated with autosomal recessive form of inherited parkinsonism. parkin encodes for E3 ubiquitin ligase, which controls the proteasome-dependent degradation or autophagy in neurons [120]. PINK1, is a mitochondrial protein kinase plays an important role in mitophagy [121, 122]. The mutations in DJ-1 bring changes in mitochondrial morphology and leads to the high production of reactive oxygen species [123]. The most common cause of autosomal recessive PD is the mutation in parkin. Parkin mutation has been reported in about 49% of familial cases and about 15% of sporadic cases [124, 125]. Mutations in DJ1 (1-8%) and PINK1 (1-2%) are less common. The function of DJ-1 is not well understood, but it protects mitochondria against the oxidative stress [126-128]. The proteins encoded by parkin, PINK1 and DJ-1 are directly or indirectly involved in the recovery of damaged mitochondria [129-131]. The other genes associated with PD are ATP13A2 [132, 133], FBXO7 [134, 135], PLA2G6 [136, 137], POLG1 [138, 139] and SYNJ1 [140, 141]. Genetic mapping methods such as linkage analysis and genome-wide association studies have been reported to be helpful in identifying new genes responsible for PD [142].

Mutations in ATP13A2 are associated with an autosomal recessive form of PD i.e. Kufor-Rakeb syndrome (KRS). It has a juvenile onset with rapid progression, followed by dementia, supranuclear gaze palsy and pyramidal signs [167, 168]. The gene consists of 29 exons, which codes for a protein of 1180 amino acids. The ATP13A2 protein is normally located in the membrane of lysosome, with 10 trans-membrane domains having an ATPase domain [169]. The first mutation in ATP13A2 (PARK9) was reported in a Chilean family [170, 171]. The lysosomal enzyme β-glucocerebrosidase is coded by GBA gene and play a role in glycolipid metabolism. Mutations in the GBA gene results in the production of non-functional β-glucocerebrosidase which leads to Gaucher disease [172]. GBA mutations are reported to enhance the progression of PD and about 8-14% of the autopsy revealed its link with PD [173-175].

The complex interactions of environmental and genetic factors may lead to PD. Such cases have been classified as sporadic [176, 177]. Damage in the substantia nigra has been reported in most of the sporadic cases [178, 179]. Some gene mutations can lead to the accumulation of unwanted protein that may alter the function of mitochondria leading to the increase in oxidative stress [180, 181]. Table 2 gives a description of genes associated with PD.

The pathogenesis of PD mainly involves dysfunction of mitochondria, protein misfolding, aggregation and oxidative stress [220]. A number of post-translational modifications (PTMs) regulates the activity of protein; for example, nitration, arginylation and N-terminal acetylation which affects the structure and behaviour of α-synuclein to interact with other biomolecules [221]. The modification of α-synuclein, its aggregation, toxicity and targets for future therapeutics has been extensively reviewed by Barrett and Greenamyre [222]. Although PTMs are required for the normal functions of α-synuclein, abnormal modifications may promote pathogenesis of the PD [223]. The phosphorylation of S129 residue has been reported to be associated with the formation of Lewy bodies [224]. Nitration of tyrosine residues in α-synuclein at Y39, Y125, Y133 and Y136 has been reported to be associated with oxidative stress [225]. Environmental factors are also responsible for the PTMs. The exposure of 1-Methyl-4-phenyl-1,2,3,6-Tetrahydropyridine (MPTP) results in the phosphorylation of S-129 in α-synuclein [226]. It has been observed that Mn induced the aggregation of α-synuclein and the similar effect was observed in cultured cells exposed to fungicide Maneb (having Mn) showed the same results [227].

Parkin, Pink1 and DJ-1 are involved in the formation of the heteromeric cytosolic complex (PPD complex) which is involved in Ubiquitin mediated proteasomal degradation [228]. It has been reported that Parkin can mediates its own ubiquitylation and give rise to high molecular mass k49-linked polyubiquitlylated moiety [229]. Phosphorylation at two different sites (T175, T217) was reported, but has not been confirmed by other researchers [230]. There are evidences that the activity of Parkin, choice of E2, choice of substrate, localization and solubility can be regulated by post-translational modification [231]. It has been reported that reactive cysteine (cys¹⁰⁶) is essential for the proper functioning of DJ1 in humans [232]. Due to the increase in oxidative stress either by aggregation of α-synuclein or environmental agents promotes the oxidation of cysteine to sulfenic, sulfinic and sulfonic acid [232]. The oxidation results in the loss of the activity of DJ-1 and thus enhances the progression of PD. The phosphorylation of LRRK2 can occur in two ways constitutive and autophosphorylation. These phosphorylations are modulated in PD [233]. The mutations in the ROCO domain (Ras of complex proteins) results in the decrease of phosphorylation at R1441C, R1441G, and Y1699C, which leads to the aggregation of LRRK2 in the substantia nigra [234]. Ubiquitination also regulates the activity of LRRK2. The mutations R1441C, R1441G and Y1699C and 12020T may result in the decrease of constitutive phosphorylation or hyper-ubiquitination or instability, leading to the formation of protein aggregates [235].

Genome wide association studies are helpful in understanding the genetic basis of PD [236]. About 24 loci have been reported to be associated significantly with the risk of disease in the individuals of European ancestry [237]. In another study, 17 novel PD loci, using a neurocentric candidate gene nomination pipeline, found that these loci play a role in lysosomal biology and autophagy [238]. The identification of such candidate genes will definitely help in understanding the role of causal genes and will also open new horizons for the therapeutic approaches.

The past half century of research has brought many alluring advancements in the treatment of PD. It is a fact that PD is a progressive disease with no permanent cure, but the symptoms can be suppressed or delayed by the treatment of levodopa [239-241]. To overcome the side effects of Levodopa, there are several treatment strategies for the management of PD in order to provide more improvement in combating the PD symptoms [242]. Various treatment strategies for the PD are as follows:

Non-pharmacological therapies includes: Deep Brain Stimulation (DBS), Gene therapy and Cell transplantation.

Since there is no permanent cure for the disease to date, a continuous efforts in the direction of treatment strategies is the need of the hour. It is difficult to differentiate between the sporadic and familial forms of PD on the basis of symptoms. Recently, the GWAS studies have paved the pathway for studying the collective role of the loci in the progression of PD. Hence, GWAS should be conducted for the better understanding of pathology as well as treatment of PD.