Biophysical studies of protein misfolding and aggregation in in vivo models of Alzheimer's and Parkinson's diseases

Abstract

Neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's diseases (PD), are characterised by the formation of aberrant assemblies of misfolded proteins. The discovery of disease-modifying drugs for these disorders is challenging, in part because we still have a limited understanding of their molecular origins. In this review, we discuss how biophysical approaches can help explain the formation of the aberrant conformational states of proteins whose neurotoxic effects underlie these diseases. We discuss in particular models based on the transgenic expression of amyloid-β (Aβ) and tau in AD, and α-synuclein in PD. Because biophysical methods have enabled an accurate quantification and a detailed understanding of the molecular mechanisms underlying protein misfolding and aggregation in vitro, we expect that the further development of these methods to probe directly the corresponding mechanisms in vivo will open effective routes for diagnostic and therapeutic interventions.

Molecular mechanisms of amyloid formation in living systems

“…These models typically display aggregation starting from early adulthood or even during development (reviewed in ref. 174 ). It will be important to investigate aggregation mechanisms in animal models expressing more modest protein levels.…”

Structural Proteomic Profiling of Cerebrospinal Fluids to Reveal Novel Conformational Biomarkers for Alzheimer’s Disease

“…Previous reports have illustrated this with amyloid-β and tau, which display significant conformational changes during the formation of amyloid plaques and NFTs, respectively, in AD cases . This is a well-documented phenomenon, with a number of reports having established AD to behave according to a prion-like mechanism, where the presence of a misfolded protein will induce a cascade of misfolding on surrounding proteins. − Current evidence also indicates the presence of insoluble aggregates in instances of AD, which are assembled of misfolded proteins. , With this evidence, it is proposed that the misfolding of currently unknown proteins occurs in an independent or synergistic way with Aβ or Tau. , Therefore, discovery of novel biomarkers based on the conformational change of proteins, other than tau and Aβ, is needed to enable early diagnosis of AD.…”

Collaboration and knowledge integration for successful brain therapeutics – lessons learned from the pandemic

“…Brain diseases are a significant cause of death worldwide and contribute significantly to years of potential life lost due to the increasing prevalence of mood, neurodevelopmental and behavior disorders in young people ( Forlund et al, 2020 ; Olfson et al, 2015 ; Liu et al, 2020 ). Recent years have seen significant advances in drug discovery and development, and approaches and technologies in central nervous system (CNS) research (as discussed in detail in, for example, Forlund et al, 2020 ; Olfson et al, 2015 ; Bloem et al, 2021 ; Sinnige et al, 2020 ; Lüscher Dias et al, 2020 ; Dhanwani et al, 2022 ; Anderson et al, 2022 ; Baird et al, 2021 ; ). Unfortunately, this progress has not been sufficiently translated into successful treatments.…”