Insights into Lewy body disease from rare neurometabolic disorders

Erskine, Daniel; Attems, Johannes

doi:10.1007/s00702-021-02355-7

Cited by 10 publications

(6 citation statements)

References 88 publications

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“… 5 , 6 As we have previously noted, α-synuclein is reported to accumulate in a number of neurometabolic diseases, although as most studies have only used pan-α-synuclein antibodies it is not clear whether such accumulations have putative pathogenic modifications associated with LBD, such as phosphorylation at serine 129 (pS129) or seed-competence, limiting inference of shared mechanisms. 7 , 8 To address this knowledge gap, we performed an observational cross-sectional study of Krabbe disease brain tissue and hypothesized that it would contain deposits of α-synuclein with prion-like attributes.…”

Section: Introductionmentioning

confidence: 99%

Prion-like α-synuclein pathology in the brain of infants with Krabbe disease

Hatton

Ghanem

Koss

et al. 2022

Brain

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Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (N = 4) compared to infant controls (N = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease.

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Section: Introductionmentioning

confidence: 99%

Prion-like α-synuclein pathology in the brain of infants with Krabbe disease

Hatton

Ghanem

Koss

et al. 2022

Brain

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“… 52 LBs are reportedly found in cases of PLAN and were confirmed through genetic testing, indicating that the PLA2G6 mutation potentially induces the aggregation of α-Syn. 52 PLAN shared similar pathological characteristics with Parkinson’s disease (PD) and Alzheimer’s disease (AD), which could be caused by the Lewy bodies present in the neurological diseases. 48 Both PKAN and PLAN involve a mutation associated with the mitochondria and lipid metabolism, which in turn could alter the regulation of iron transport and utilization in the brain.…”

Section: Genetic Targetsmentioning

confidence: 84%

“…Axonal spheroids are bead-like swellings along axons and are a frequent characteristic of axonal degeneration . Lewy bodies (LBs) are commonly found in many neurodegenerative diseases and are made up of aggregated forms of the protein alpha-synuclein (α-Syn), which form beta-sheet-rich amyloid fibrils that contribute to the pathology of the diseases . LBs are reportedly found in cases of PLAN and were confirmed through genetic testing, indicating that the PLA2G6 mutation potentially induces the aggregation of α-Syn .…”

Section: Genetic Targetsmentioning

confidence: 99%

“…Lewy bodies (LBs) are commonly found in many neurodegenerative diseases and are made up of aggregated forms of the protein alpha-synuclein (α-Syn), which form beta-sheet-rich amyloid fibrils that contribute to the pathology of the diseases . LBs are reportedly found in cases of PLAN and were confirmed through genetic testing, indicating that the PLA2G6 mutation potentially induces the aggregation of α-Syn . PLAN shared similar pathological characteristics with Parkinson’s disease (PD) and Alzheimer’s disease (AD), which could be caused by the Lewy bodies present in the neurological diseases .…”

Section: Genetic Targetsmentioning

confidence: 99%

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Genetic Targets and Applications of Iron Chelators for Neurodegeneration with Brain Iron Accumulation

Marupudi,

Xiong

2024

ACS Bio Med Chem Au

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Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative diseases that are typically caused by a monogenetic mutation, leading to development of disordered movement symptoms such as dystonia, hyperreflexia, etc. Brain iron accumulation can be diagnosed through MRI imaging and is hypothesized to be the cause of oxidative stress, leading to the degeneration of brain tissue. There are four main types of NBIA: pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MKAN), and beta-propeller protein-associated neurodegeneration (BPAN). There are no causative therapies for these diseases, but iron chelators have been shown to have potential toward treating NBIA. Three chelators are investigated in this Review: deferoxamine (DFO), desferasirox (DFS), and deferiprone (DFP). DFO has been investigated to treat neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD); however, dose-related toxicity in these studies, as well as in PKAN studies, have shown that the drug still requires more development before it can be applied toward NBIA cases. Iron chelation therapies other than the ones currently in clinical use have not yet reached clinical studies, but they may possess characteristics that would allow them to access the brain in ways that current chelators cannot. Intranasal formulations are an attractive dosage form to study for chelation therapy, as this method of delivery can bypass the blood-brain barrier and access the CNS. Gene therapy differs from iron chelation therapy as it is a causal treatment of the disease, whereas iron chelators only target the disease progression of NBIA. Because the pathophysiology of NBIA diseases is still unclear, future courses of action should be focused on causative treatment; however, iron chelation therapy is the current best course of action.

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“…Lewy body disease is a pathologic term for neurodegenerative disorders characterized by aggregated α-synuclein in perikarya and neurites of neurons (Lewy bodies and Lewy neurites) [ 4 ]. Lewy body pathology is not restricted to Parkinson’s disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB), but is also observed in several neurodevelopmental and neurometabolic disorders, such as PLA2G6 -associated neurodegeneration (i.e., infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, adult-onset dystonia-parkinsonism, and autosomal recessive early-onset parkinsonism), POLG -associated neurodegeneration, Niemann-Pick type C1, and Krabbe disease [ 5 ]. Although these diseases have α-synuclein aggregates at a much younger age than incidental Lewy bodies observed in other neurodegenerative disorders or healthy elderly individuals, these disorders are not included in this review.…”

Section: Introductionmentioning

confidence: 99%

Neuropathology and molecular diagnosis of Synucleinopathies

Koga

Sekiya

Kondru

et al. 2021

Mol Neurodegeneration

168

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Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions. Synucleinopathies can be divided into two major disease entities: Lewy body disease and multiple system atrophy (MSA). Common clinical presentations of Lewy body disease are Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia and MSA with predominant parkinsonism. There are currently no disease-modifying therapies for the synucleinopathies, but information obtained from molecular genetics and models that explore mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and glial cytoplasmic inclusions) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from Lewy body disease and MSA are distinct “strains” having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a discussion of the evolution of classification and staging of Lewy body disease. We also provide a brief discussion on proposed mechanisms of Lewy body formation, as well as evidence supporting the existence of distinct α-synuclein strains in Lewy body disease and MSA.

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Insights into Lewy body disease from rare neurometabolic disorders

Cited by 10 publications

References 88 publications

Prion-like α-synuclein pathology in the brain of infants with Krabbe disease

Prion-like α-synuclein pathology in the brain of infants with Krabbe disease

Genetic Targets and Applications of Iron Chelators for Neurodegeneration with Brain Iron Accumulation

Neuropathology and molecular diagnosis of Synucleinopathies

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