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Accumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

Accumulation of alpha-synuclein protein aggregates is the hallmark neuropathologic feature of synucleinopathies such as Parkinson's disease. Rare point mutations and multiplications in SNCA, the gene encoding alpha-synuclein, as well as other genetic alterations are linked to familial Parkinson's disease cases with high penetrance and hence constitute major genetic risk factors for Parkinson's disease. However, the preponderance of cases seems sporadic, most likely based on a complex interplay between genetic predispositions, aging processes and environmental influences. Deciphering the impact of these environmental factors and their interactions with the individual genetic background in humans is challenging and often requires large cohorts, complicated study designs, and longitudinal set-ups. In contrast, rodent models offer an ideal system to study the influence of individual environmental aspects under controlled genetic background and standardized conditions. In this review, we highlight findings from studies examining effects of environmental enrichment mimicking stimulation of the brain by its physical and social surroundings as well as of environmental stressors on brain health in the context of Parkinson's disease. We discuss possible internal molecular transducers of such environmental cues in Parkinson's disease rodent models and emphasize their potential in developing novel avenues to much-needed therapies for this still incurable disease. This article is part of the Special Issue "Synuclein". peerReviewed

Intracellular vesicular trafficking is essential for neuronal development, function, and homeostasis and serves to process, direct, and sort proteins, lipids, and other cargo throughout the cell. This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death. Critically, RAB39B loss-of-function mutations are known to be associated with X-linked intellectual disability and with rare early-onset Parkinson's disease. Moreover, recent studies have highlighted altered RAB39B expression in idiopathic cases of several Lewy body diseases (LBDs). This review contextualizes the role of RAB proteins in LBDs and highlights the consequences of RAB39B impairment in terms of endosomal trafficking, neurite outgrowth, synaptic maturation, autophagy, as well as alpha-synuclein homeostasis. Additionally, the potential for therapeutic intervention is examined via a discussion of the recent progress towards the development of specific RAB modulators. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients worldwide. Both diseases share, as a common hallmark, the accumulation of characteristic protein aggregates, known as Lewy bodies (LB) in PD, and neurofibrillary tangles in AD. LBs are primarily composed of misfolded α-synuclein (aSyn), and neurofibrillary tangles are primarily composed of tau protein. Importantly, upon pathological evaluation, most AD and PD/Lewy body dementia cases exhibit mixed pathology, with the co-occurrence of both LB and neurofibrillary tangles, among other protein inclusions. Recent studies suggest that both aSyn and tau pathology can spread and propagate through neuronal connections. Therefore, it is important to investigate the mechanisms underlying aggregation and propagation of these proteins for the development of novel therapeutic strategies. Here, we assessed the effects of different pharmacological interventions on the aggregation and internalization of tau and aSyn. We found that anle138b and fulvic acid decrease aSyn and tau aggregation, that epigallocatechin gallate decreases aSyn aggregation, and that dynasore reduces tau internalization. Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of aSyn and tau will be important for the development of future therapeutic interventions.

Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated α-synuclein into the Lewy bodies present in Parkinson's disease. Of the various chaperones known to be associated with neurodegenerative disease, the small secretory chaperone known as proSAAS (named after four residues in the amino terminal region) has many attractive properties. We show here that proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson's disease. Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in an in vitro assay; residues 158-180, containing a largely conserved element, are critical to this bioactivity. ProSAAS also exhibits a neuroprotective function; proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein-induced cytotoxicity in SH-SY5Y cells. Four independent proteomics studies have previously identified proSAAS as a potential cerebrospinal fluid biomarker in various neurodegenerative diseases. Coupled with prior work showing that proSAAS blocks β-amyloid aggregation into fibrils, this study supports the idea that neuronal proSAAS plays an important role in proteostatic processes. ProSAAS thus represents a possible therapeutic target in neurodegenerative disease.

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Presently, there is no causal therapy available to slow down or halt disease progression. The presynaptic protein alpha-synuclein aggregates to form intraneuronal Lewy bodies in PD. It is generally believed that intermediates on the way from monomers to the large aggregates would mediate neurotoxicity, but the precise species and mechanism responsible for neuronal death are controversially debated. To study alpha-synuclein-mediated toxicity, we developed a new model in which moderate overexpression of wild-type alpha-synuclein led to gradual death of human postmitotic dopaminergic neurons. In accordance with findings in postmortem PD brains, small oligomeric species occurred and the autophagic flux was impaired in our model. The phenothiazine neuroleptic trifluoperazine, an activator of macroautophagy, selectively reduced one particular alpha-synuclein species and rescued cells. Inversely, blocking of autophagy led to an accumulation of this oligomeric species and increased cell death. These data show that activation of autophagy is a promising approach to protect against alpha-synuclein pathology and likely acts by targeting one specific alpha-synuclein species.