The prevalence of age-dependent disorders is estimated to significantly increase by 2050, yet there are currently no effective treatments that can halt their progression. Among these conditions, Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder (NDD) after Alzheimer's disease (AD), primarily affecting movement and motor coordination (Kulkarni et al., 2023; Sharma and Singh, 2020). PD affects approximately 1–2 % of people age 65 and older, with incidence rising to 4–5 % among those 80 years or older. It is a chronic progressive NDD condition that gradually worsens over time. Like other NDDs, PD is also characterized by protein misfolding and aggregation (Sharma et al., 2021). It is marked by two key features: deposition of abnormal protein clumps called Lewy bodies (protein inclusions primarily composed of misfolded α-synuclein) and the early loss of brain cells specifically dopaminergic neurons in a specific region of brain (substantia nigra pars compacta (SNpc)) (Bayati and McPherson, 2024). This neurodegeneration causes dopamine deficiency in a brain area crucial for movement control (basal ganglia) ultimately resulting in classical Parkinsonian motor symptoms including slow movement, tremor, stiffness and eventually postural instability (Radhakrishnan and Goyal, 2018). In pathological conditions, normally soluble α-syn undergoes structural changes forming β-sheet interactions that lead to toxic insoluble amyloid structures, disrupting cellular homeostasis and ultimately leading causing neuronal death. The exact cause of PD remains incompletely understood, but scientists believe it develops from a complex interaction between multiple factors: natural aging process, inherited genetic traits and various ecological factors. However, multiple genes directly implicated in proteostasis disruption contribute to PD pathogenesis: SNCA (mutations lead to α-syn overproduction and misfolding, accelerating Lewy body formation and overwhelming protein clearance systems), leucine-rich repeat kinase 2 (LRRK-2) (mutations impair vesicular transport and microtubule dynamics, disrupting efficient protein trafficking and degradation pathways), and GBA (mutations reduce glucocerebrosidase activity, compromising lysosomal function and α-syn degradation, which causes toxic protein accumulation) (Tanaka and Matsuda, 2014). Additionally, mutations in protein deglycase (DJ-1) impair oxidative stress responses and chaperone activity, while PARKIN and PTEN-induced putative kinase 1 (PINK1) mutations disrupt mitochondrial quality control (MQC) and mitophagy, leading to defective protein degradation and cellular energy deficits all of which have established causative role in PD pathogenesis (Franco et al., 2021), shown in Table 1.

Therefore, preserving protein balance (proteostasis) within cells by regulating the balance protein folding and misfolding, is crucial for preserving the functionality of the proteome (Kurtishi et al., 2019). Proteostasis encompasses cellular mechanisms ensuring quality protein synthesis, precise protein biogenesis, enabling accurate trafficking and folding (Gandhi et al., 2019). It is maintained through a complex network known as proteostasis network (PN), which encompasses posttranslational modifications (PTMs), molecular chaperones along with two primary degradation pathways involving main degradation systems like the proteasome and autophagy. These systems work together to breakdown and remove damaged and misfolded proteins in cells. The proteasome, working with an intricate ubiquitin system (which tags proteins for destruction), selectively breaks down short-lived regulatory proteins crucial for maintaining cellular homeostasis, as well as misfolded or damaged proteins that could be harmful if they aggregate (Cerri and Blandini, 2019). The dysfunction of proteasomes extends beyond protein clearance and impacting cellular stress management, particularly in oxidative and mitochondrial contexts. When cells experience oxidative stress, proteasomes play a crucial role by eliminating proteins that has been damaged (Feng et al., 2024; Selvaraj and Piramanayagam, 2019). However, In PD the mitochondrial dysfunction creates excessive oxidative stress, which overwhelms the proteasomes ability to keep up with clearing out these damaged proteins (Höhn et al., 2020a). Moreover, proteasomal dysfunction contributes to neuroinflammatory processes a key critical aspect of PD pathogenesis. This article provides a detailed examination of the interplay between PTMs and proteostasis, Chaperones and proteostasis, Unfolded Protein Response (UPR) and proteostasis, Ubiquitin-Proteasome System (UPS) and proteostasis along with Autophagy-Lysosomal Pathway (ALP) and proteostasis, showing how they work together to maintain cellular homeostasis and prevent pathogenic protein aggregate accumulation. Moreover, this review article explores various therapeutic approaches of PTMs, chaperones, UPR, UPS and autophagy mediated processes of proteostasis that plays a neuroprotective role in PD. Eventually, advancing understanding of the underlying mechanism of PTMs, chaperones, UPR, UPS and autophagy in proteostasis in PD provides new possibilities for treatments and future research directions.