Parkinson's

1.
In 1817, James Parkinson published his monograph titled An Essay on the Shaking Palsy
which represents the first description of PD as a neurological disorder. Parkinson’s disease
(PD) is the second most common neurodegenerative disease worldwide, and its treatment
remains a big challenge.
2. The pathogenesis of PD may be related to environmental and genetic factors, and exposure
to toxins and gene mutations may be the beginning of brain lesions.
3. The identified mechanisms of PD include α-synuclein aggregation, oxidative stress,
ferroptosis, mitochondrial dysfunction, neuroinflammation, and gut dysbiosis.
4. There are two main kinds of PD: (1) tremor-dominant PD and (2) non-tremor-dominant
PD, based on clinical findings.
5. Tremor-dominant PD is frequently linked to a slower pace of development and less
functional impairment. Patients with PD have a variety of motor symptoms, including
bradykinesia, muscle stiffness, rest tremor, and postural and gait difficulties.
6. Non-tremor-dominant PD is characterized by Olfactory dysfunction, cognitive decline,
constipation, depression, sleep problems such as excessive daytime drowsiness and rapid
eye movement sleep behavior disorder, autonomic dysfunction, pain, and exhaustion and
frequently appear in the early stages of PD before the motor symptoms.
7. The primary pathogenic characteristics of PD include the steady degradation of just a subset of
neurons within particular brain areas, such as the SN, as the illness progresses. Dopaminergic neurons
are lost exclusively in the ventrolateral SN in the early stages; however, this damage spreads in the late
stages.
8. Etiology and pathogenesis of PD
(i) Environment genetic factors: Human epidemiological studies have implicated residence in a rural
environment and related exposure to herbicides and pesticides with an elevated risk of PD.
Environmental causes are situations such as pesticide exposure, physical inactivity, head injury, and
stress. People intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydrodropyridine (MPTP) developed a
syndrome nearly identical to PD and its active metabolite, 1-methyl-4-phenylpyridinium (MPP +), is
similar to PD.
(ii) Autosomal-dominant PD genes: The most frequent genetic cause of PD is a mutation in the
leucine-rich repeat kinase 2 gene (LRRK2), known as PARK8. LRRK2 mutations have primarily been
found in late-onset individuals older than 50 years.
Patients with SNCA mutations whose brains showed the aggregation of α-synuclein, represented as the
occurrence of Lewy bodies and the loss of DA neurons, that the PARK1/PARK4 gene for the expression
of α-synuclein is related to the abnormal pathological aggregation of insoluble α-synuclein fibril.
The most common variations of this mutation are G2019S, R1441C, R1441G, and R1441H, which can
cause DA neurons to die and degenerate by interfering with a variety of physiological processes,
including vesicle transport, cytoskeletal function, protein synthesis, and the lysosomal system.
(iii) Autosomal-recessive PD genes: The most frequent cause of autosomal-
recessive early-onset Parkinson’s syndrome is PARK2, which is encoded by the
parkin RBR E3 ubiquitin protein ligase gene (PRKN). In the ubiquitin–proteasome
system, which is thought to be a multipurpose neuroprotective agent against a
variety of toxic injuries, including mitochondrial poisons, and is thought to be
essential for the survival of DA neurons. According to studies, the PARK2
mutation is present in up to 7% of PD patients between 30 and 35 years old and
as much as 50% of PD cases over 25 years old.
Molecular mechanisms of PD
1) α-synuclein aggregation 6) Neuroinflammation
2) Oxidative stress 7) Gut dysbiosis
3) Ferroptosis 8)
4) Mitochondrial dysfunction
1. α-synuclein aggregation:
α-synuclein is a potential chaperone that plays a role in the dynamics of
synaptic vesicles, intracellular trafficking, and mitochondrial function. Abnormal
α-synuclein aggregation is one of the most important hypotheses explaining the
death of nigrostriatal neurons in PD.
α-synuclein itself can become neurotoxic when soluble α-synuclein
monomers form oligomers, which combine into tiny protofibrils and eventually
form large, insoluble fibrils.
Age-related decline in proteolytic defense mechanisms of the brain may
play an important role in α-synuclein accumulation. Specifically, intracellular α-
synuclein homeostasis is maintained by the ubiquitin–proteasome and lysosomal
autophagy systems.
• Oxidative stress
Oxidative stress (OS) is a major process in aging that directly harms the
CNS. Under physiological conditions, free radicals or ROS are important to host
defense, gene transcription, synaptic plasticity regulation, and apoptosis.
OS occurs when ROS overwhelms cellular antioxidant activity. Cytotoxic
compounds then accumulate to cause protein collapse, enzyme failure, lipid
breakdown, and cell death in various neurons, including DA-neuronal tissue.
These dysfunctions contribute to PD pathogenesis, and may also be a cause
of Alzheimer’s disease (AD).
1) NADPH oxidase (NOX) is considered the most important ROS generator, 90
playing a crucial role in triggering OS and neurotoxicity.
2) Superoxide radical, the Fenton reaction, which severely oxidizes DNA or
lipids, can cause hydrogen peroxide to transform into a highly reactive
hydroxyl radical, ferroptosis is connected to the imbalance of iron ion
homeostasis, implying a connection between ferroptosis and OS, Depletion of
glutathione.

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