Chaperone-Based Therapies for Disease Modification in Parkinson’s Disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by the presence of pathological intracellular aggregates primarily composed of misfolded α-synuclein. This pathology implicates the molecular machinery responsible for maintaining protein homeostasis (proteostasis), including molecular chaperones, in the pathobiology of the disease. There is mounting evidence from preclinical and clinical studies that various molecular chaperones are downregulated, sequestered, depleted, or dysfunctional in PD. Current therapeutic interventions for PD are inadequate as they fail to modify disease progression by ameliorating the underlying pathology. Modulating the activity of molecular chaperones, cochaperones, and their associated pathways offers a new approach for disease modifying intervention. This review will summarize the potential of chaperone-based therapies that aim to enhance the neuroprotective activity of molecular chaperones or utilize small molecule chaperones to promote proteostasis.

Alpha-B-Crystallin Effect on Mature Amyloid Fibrils: Different Degradation Mechanisms and Changes in Cytotoxicity

“…Scheme shows the ability of alpha-B-crystallin to inhibit the formation of pathological amyloid fibrils [ 20 , 36 , 37 ]. This ability allowed early proposal of the chaperones-based therapy of amyloidosis on their initial stages (see, for example, the review [ 24 ]). However, since these diseases are often diagnosed at the later stages when a large amount of amyloids is already accumulated in the patient’s body, we pay attention to chaperones’ influence on mature amyloid fibrils.…”

“…In a number of other works, the possibility of activation of the process of amyloid fibrils formation and a reduction in the duration of the lag phase by chaperones at their substoichiometric concentrations, in comparison with fibrillogenesis in the absence of chaperones, has been shown [ 22 , 23 ]. Nevertheless, as we already noted, according to the results of most studies of the chaperones and chaperon-like proteins’ effect on fibrillogenesis, these proteins can be specifically and effectively targeted to slow or prevent amyloid disease progression (see, for example, the review [ 24 ]).…”

The making of a Lewy body: the role of alpha-synuclein post-fibrillization modifications in regulating the formation and the maturation of pathological inclusions.

“…Finally, WB analyses of human tissues extracted from MSA brain patients ( Figure S5F) clearly revealed C-terminally truncated α-syn, which was detected with an N-terminal antibody (epitope: [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] or the human specific antibody (clone 4B12, epitope: 103-108), but not with an antibody specific for the C-terminal domain (epitope: 134-138) ( Figure 2E). Altogether, our data demonstrate that the truncation of α-syn fibrils is a general and early event that occurs during the formation of intracellular LB-like α-syn inclusions in all neuronal seeding models tested and, even more importantly, in brain tissues from MSA patients.…”

“…Our findings suggest that the formation of α-syn inclusions in the context of the neuronal seeding requires a sequence of events starting with 1) the internalization and cleavage of PFF seeds followed by 2) the initiation of the seeding and 3) fibril elongation along with the incorporation of PTMs such as phosphorylation at residue S129. We hypothesized that the Hsp70 disaggregase-associated chaperones complex (Hsc70, DNAJB1 and Hsp110) can disassemble α-syn fibrils into non-toxic monomers or into shorted aggregates that can be degraded by the autophagic and/or the proteasomal pathway, which reduces the level of aggregates in cells15 . Failure of the degradation machineries and/or disruption of α-syn interactions with molecular chaperones would result in the accumulation of fibrils in the cytosol, which in turn could lead to aberrant interactions with cellular partners.…”

Co‐expression with chaperones can affect protein 3D structure as exemplified by loss‐of‐function variants of human prolidase

“…They also play a role in refolding of misfolded proteins and can help in dissolving protein aggregates and target misfolded proteins for degradation [18]. Several approaches to modulate chaperone activity were developed and investigated primarily in neurodegenerative disorders [19,20], and the pharmacological induction of chaperone proteins was recently shown to be a potent way of ameliorating amyloidlike aggregation involving protein kinase Cc [21]. Chaperone co-expression is often also advantageous for heterologous protein expression [22][23][24].…”