Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease: From Protein Aggregates to Synaptic Dysfunction

Compta, Yaroslau; Révész, Tamás

doi:10.3233/jpd-202323

Cited by 38 publications

(34 citation statements)

References 114 publications

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“…In monogenic PD, neuropathological findings of synuclein deposition range from being characteristic of SNCA mutations (Duda et al., 2002) to relatively uncommon in cases with PRKN mutations (Seike et al., 2021) and are frequently variable in LRRK2 mutations (Wszolek et al., 2004). LBs are not restricted to cases of PD, as Lewy‐type pathology is well described in Alzheimer's disease, both sporadic and genetic forms (Compta & Revesz, 2021). Many cases of sporadic PD likely arise in patients with an incidental “Lewy Body State” (de la Fuente‐Fernandez et al., 1998).…”

Section: α‐Synuclein Found In the Gut Of Pd Patientsmentioning

confidence: 99%

Movement of prion‐like α‐synuclein along the gut–brain axis in Parkinson's disease: A potential target of curcumin treatment

Chetty

Abrahams

Coller

et al. 2021

Eur J of Neuroscience

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A pathological hallmark of the neurodegenerative disorder, Parkinson's disease (PD), is aggregation of toxic forms of the presynaptic protein, α-synuclein in structures known as Lewy bodies. α-Synuclein pathology is found in both the brain and gastrointestinal tracts of affected individuals, possibly due to the movement of this protein along the vagus nerve that connects the brain to the gut. In this review, we discuss current insights into the spread of α-synuclein pathology along the gut-brain axis, which could be targeted for therapeutic interventions. The prion-like propagation of α-synuclein, and the clinical manifestations of gastrointestinal dysfunction in individuals living with PD, are discussed. There is currently insufficient evidence that surgical alteration of the vagus nerve, or removal of gut-associated lymphoid tissues, such as the appendix and tonsils, are protective against PD. Furthermore, we propose curcumin as a potential candidate to prevent the spread of α-synuclein pathology in the body by curcumin binding to α-synuclein's non-amyloid β-component (NAC) domain. Curcumin is an active component of the food spice turmeric and is known for its antioxidant, anti-inflammatory, and potentially neuroprotective properties. We hypothesize that once α-synuclein is bound to curcumin, both molecules are subsequently excreted from the body. Therefore, dietary supplementation with curcumin over one's lifetime has potential as a novel approach to complement existing PD treatment and/or prevention strategies. Future studies are required to validate this hypothesis, but if successful, this could represent a significant step towards improved

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Section: α‐Synuclein Found In the Gut Of Pd Patientsmentioning

confidence: 99%

Movement of prion‐like α‐synuclein along the gut–brain axis in Parkinson's disease: A potential target of curcumin treatment

Chetty

Abrahams

Coller

et al. 2021

Eur J of Neuroscience

View full text Add to dashboard Cite

show abstract

“…PD and Alzheimer's disease (AD) are the two most common neurodegenerative disorders and share some pathological traits, such as misfolding, aggregation, and widespread accumulation of natively unfolded proteins [85][86][87]. Amyloid beta (Aβ) deposits into extracellular Aβ plaques and the hyperphosphorylation of Tau protein, leading to the formation of neurofibrillary tangles (NFT) inside neurons, are specific alterations of AD [88].…”

Section: β-Amyloid and P-tau Pathologymentioning

confidence: 99%

Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson’s Disease: Roads to Biomarker Discovery

et al. 2021

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Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery.

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“…Soon after, α-synuclein, the protein product of SNCA , was identified as the major constituent of Lewy bodies [ 166 ]. The aggregation propensity of α-synuclein and its involvement in neurodegenerative diseases had already been reported, albeit without being recognised as α-synuclein, as it had previously been associated with the non-amyloid component of plaques in AD patients [ 234 ], who frequently develop Lewy bodies [ 109 , 235 ]. Since 1997, six SNCA missense mutations, as well as gene duplications and triplications have been linked to dominantly inherited PD and dementia, suggesting that an increase not only in the aggregation tendency but also in the expression level of α-synuclein can induce toxicity [ 236 ].…”

Section: Modelling α-Synuclein Pathology In C Elegans To Dissect Pd Gene Functionmentioning

confidence: 99%

Modelling the functional genomics of Parkinson’s disease inCaenorhabditis elegans:LRRK2and beyond

et al. 2021

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For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans, show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes.

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Neuropathological and Biomarker Findings in Parkinson’s Disease and Alzheimer’s Disease: From Protein Aggregates to Synaptic Dysfunction

Cited by 38 publications

References 114 publications

Movement of prion‐like α‐synuclein along the gut–brain axis in Parkinson's disease: A potential target of curcumin treatment

Movement of prion‐like α‐synuclein along the gut–brain axis in Parkinson's disease: A potential target of curcumin treatment

Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson’s Disease: Roads to Biomarker Discovery

Modelling the functional genomics of Parkinson’s disease inCaenorhabditis elegans:LRRK2and beyond

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