Cross-talks among GBA mutations, glucocerebrosidase, and α-synuclein in GBA-associated Parkinson’s disease and their targeted therapeutic approaches: a comprehensive review

Abstract

Current therapies for Parkinson’s disease (PD) are palliative, of which the levodopa/carbidopa therapy remains the primary choice but is unable to modulate the progression of neurodegeneration. Due to the complication of such a multifactorial disorder and significant limitations of the therapy, numerous genetic approaches have been proved effective in finding out genes and mechanisms implicated in this disease. Following the observation of a higher frequency of PD in Gaucher’s disease (GD), a lysosomal storage condition, mutations of glycosylceramidase beta (GBA) encoding glucocerebrosidase (GCase) have been shown to be involved and have been explored in the context of PD. GBA mutations are the most common genetic risk factor of PD. Various studies have revealed the relationships between PD and GBA gene mutations, facilitating a better understanding of this disorder. Various hypotheses delineate that the pathological mutations of GBA minimize the enzymatic activity of GCase, which affects the proliferation and clearance of α-synuclein; this affects the lysosomal homeostasis, exacerbating the endoplasmic reticulum stress or encouraging the mitochondrial dysfunction. Identification of the pathological mechanisms underlying the GBA-associated parkinsonism (GBA + PD) advances our understanding of PD. This review based on current literature aims to elucidate various genetic and clinical characteristics correlated with GBA mutations and to identify the numerous pathological processes underlying GBA + PD. We also delineate the therapeutic strategies to interfere with the mutant GCase function for further improvement of the related α-synuclein–GCase crosstalks. Moreover, the various therapeutic approaches such as gene therapy, chaperone proteins, and histone deacetylase inhibitors for the treatment of GBA + PD are discussed.

Multifaceted Role of Matrix Metalloproteinases in Neurodegenerative Diseases: Pathophysiological and Therapeutic Perspectives

“…TIMPs and MMPs were found to encourage the lesions' evolution. In addition, MMPs are well-known to be produced in large amounts at the sites of lesions by immune cells of effected areas, and TIMPs might regulate the MMP activity, indicating that TIMPs' deregulation also results in AD progression [223,224]. The importance of MMPs in AD is not well established [225][226][227].…”

Reconstruction of the Cytokine Signaling in Lysosomal Storage Diseases by Literature Mining and Network Analysis

“…Similarly, NR3C1 has been associated with epigenetic deregulations in Parkinson’s disease ( Fernández-Santiago et al, 2015 ). Since GD patients are at higher risk of developing Parkinson’s disease ( Behl et al, 2021 ), this finding deserves further investigation.…”

The Footprint of Kynurenine Pathway in Neurodegeneration: Janus-Faced Role in Parkinson’s Disorder and Therapeutic Implications

“…The dopaminergic metabolism in bipolar disorder, depression, and schizophrenia, has been reported to be impaired by KMO gene polymorphism [105]. The significant involvement of SNPs of KMO were investigated in PD [16,106]. However, the study was unable to recognize any relationship of the four SNPs investigated in PD and were unable to carry the binding sites for regulatory proteins, associated with PD pathogenesis [106].…”

“…Numerous targets have been identified to facilitate PD treatment, such as chaperones, protein Abelson (c-Abl), glucocerebrosidase-1 (GBA-1), calcium, neuromelanin, ubiquitinproteasome system (UPS), neuroinflammation, mitochondrial dysfunction, and KP. Chaperones are the protein entities that are elevated as a response to temperature, due to which they are also referred to as heat shock proteins (HSP) [2,106]. These regulate folding, refolding and degradation of proteins, thereby sustaining proteostasis.…”