Parkinson’s disease: etiopathogenesis and treatment

Abstract

The concept of ‘idiopathic’ Parkinson’s disease (PD) as a single entity has been challenged with the identification of several clinical subtypes, pathogenic genes and putative causative environmental agents. In addition to classic motor symptoms, non-motor manifestations (such as rapid eye movement sleep disorder, anosmia, constipation and depression) appear at prodromic/premotor stage and evolve, along with cognitive impairment and dysautonomia, as the disease progresses, often dominating the advanced stages of the disease. The key molecular pathogenic mechanisms include α-synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (associated with deficient ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. The involvement of dopaminergic as well as noradrenergic, glutamatergic, serotonergic and adenosine pathways provide insights into the rich and variable clinical phenomenology associated with PD and the possibility of alternative therapeutic approaches beyond traditional dopamine replacement therapies.One of the biggest challenges in the development of potential neuroprotective therapies has been the lack of reliable and sensitive biomarkers of progression. Immunotherapies such as the use of vaccination or monoclonal antibodies directed against aggregated, toxic α-synuclein.as well as anti-aggregation or protein clearance strategies are currently investigated in clinical trials. The application of glucagon-like peptide one receptor agonists, specific PD gene target agents (such as GBA or LRRK2 modifiers) and other potential disease modifying drugs provide cautious optimism that more effective therapies are on the horizon. Emerging therapies, such as new symptomatic drugs, innovative drug delivery systems and novel surgical interventions give hope to patients with PD about their future outcomes and prognosis.

Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

“…Specifically, the death of dopaminergic neurons that project from the substantia nigra pars compacta to the caudate-putamen in the striatum results in the loss of dopamine neurotransmission, causing the primary motor symptoms, including tremor at rest, bradykinesia, rigidity and postural instability. Although PD was initially described as a movement disorder without dementia, it is now accepted that PD progression affects other extra-nigral dopaminergic, cholinergic and serotoninergic tracts, leading to nonmotor symptoms that include anosmia, sleep disorders and constipation as well as cognitive and psychiatric symptoms, such as dementia and depression [ 1 , 2 ].…”

R1441G but not G201S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils

“…The greatest unmet need in PD are disease modifying treatments that slow or stop disease progression which is further highlighted by the projected doubling of PD cases over the next 20 years ( 1 ). While the underlying cause for PD is largely unknown, the discovery of rare genetic forms of the condition has provided crucial insight into pathomechanistic processes altered in PD that have been leveraged for devising novel targeted treatment strategies( 3 ).…”

GBA-Associated Synucleinopathies: Prime Candidates for Alpha-Synuclein Targeting Compounds

“…Subsequently, molecular pathways associated with alpha-synuclein clearance, aggregation, and propagation have been detected. Next to defects in vesicular trafficking, mitochondrial and importantly lysosomal dysfunction represent the most relevant pathways (Jankovic and Tan, 2020). Studying these likely early and initiating events provides "entry points" to develop novel therapeutic targets on an individualized basis.…”