<scp>TDP</scp>‐43 Proteinopathy Presenting with Typical Symptoms of Parkinson's Disease

Yamashita, Ryo; Beck, Goichi; Yonenobu, Yuki; Inoue, Koichiro; Mitsutake, Akihiko; Ishiura, Hiroyuki; Hasegawa, Masato; Murayama, Shigeo; Mochizuki, Hideki

doi:10.1002/mds.29048

Cited by 16 publications

(10 citation statements)

References 7 publications

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“…However, several reports indicated that significant neurodegeneration and cellular dysfunction precede Lewy pathology emerging in the substantia nigra, suggesting these two events may not be pathologically linked[5, 7, 31, 40]. Further, there are emerging data from LRRK2 [30, 35] and other cases [58], that support the presence of clinical PD without synuclein pathology. Further, in support of this concept, subjects with Braak PD stages 1 and 2 exhibit dopaminergic neuronal dysfunction and neuronal loss, even though Lewy body pathology is undetectable in the substantia nigra[5, 40].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…This suggests that neurodegeneration and neuronal dysfunction precede alpha synuclein(α-syn) positive Lewy pathology in the substantia nigra. Furthermore, Lewy pathology is not always detected in the substantia nigra of PD and parkinsonian brains[6, 7, 35, 40, 58], indicating that there is an early non-synuclein pathologic process involved in PD nigrostriatal degeneration, challenging the central pathogenic role of α-syn.…”

Section: Introductionmentioning

confidence: 99%

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Is Tau the Initial Pathology in Dopaminergic Nigrostriatal Degeneration? Studies in Parkinsonism and Parkinson’s Disease

Chu

Hirst

Federoff

et al. 2022

Preprint

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While Parkinson ′ disease(PD) remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that PD consists of multiple pathologies, but it is unclear which occurs first and which are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits (MMD). Motor deficits were determined on a modified and validated Unified Parkinson ′ Disease Rating Scale III (UPDRS III), but they occur to a degree insufficient to diagnose PD. We consider this population to have prodromal PD. However, in past studies, cases in this cohort had a selection bias as both a clinical syndrome in between no motor deficits and PD, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in this study, we only based inclusion on a clinical phenotype intermediate between no motor impairment and PD. Then, we divided this group further based upon whether or not they had a synucleinopathy. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation, loss of TH-phenotype in the substantia nigra and putamen, and changes in axonal transport occur equally in groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8-expressing phospho-tau, a pathology not seen in the nigrostriatal system of aged-matched controls. These finding were confirmed with early (CP13) and late (PHF1) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and is likely tau mediated.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Is Tau the Initial Pathology in Dopaminergic Nigrostriatal Degeneration? Studies in Parkinsonism and Parkinson’s Disease

Chu

Hirst

Federoff

et al. 2022

Preprint

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“…A recent case report described an individual who was thoroughly examined and clinically diagnosed with PD but showed no alpha-synuclein inclusions in any brain region at post-mortem analysis. Rather, phosphorylated TDP-43 protein accumulation was abundant in the SN and in other areas of the brain [83]. These examples suggest that alpha-synuclein accumulation and aggregation may simply be an indicator of cellular dysfunction e.g., autophagic dysregulation, not the culprit that initiates or drives dopaminergic dysfunction in idiopathic PD.…”

Section: Discussionmentioning

confidence: 99%

New insights underlying the early events of dopaminergic dysfunction in Parkinson’s Disease

Cruz

2020

Preprint

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We now show that key processes implicated in synuclein pathogenesis such as impairment of cellular autophagy and alpha-synuclein (α-syn) aggregation are induced by alpha-melanocyte stimulating hormone (alpha-MSH), a microglia-secreted anti-inflammatory mediator. We employed the pigmented melanoma cell line MNT-1 as a novel in-vitro cell model of melanin-containing dopaminergic neurons (DNs) of the substantia nigra (SN). Melanin levels serve as a reliable readout of autophagy in MNT-1 and exposure to alpha-MSH resulted in a decrease in melanin and a failure to slow down glucose consumption, which induced cell death by apoptosis. ASIP (agouti-signaling protein), the natural biologic inhibitor of alpha-MSH, blocked and reversed the effects of alpha-MSH. Mice administered intranasal alpha-MSH exhibited progressive decline in gait, a prevalent condition seen in patients with Parkinson’s Disease (PD). Moreover, we observed what may be α-syn aggregation in the SN pars compacta (SNpc). SNpc and striatal tyrosine hydroxylase (TH) density showed very modest reduction in this animal PD model consistent with PD pathology at the very early stage of disease.Fundamental Questions Addressed by this StudyWhat may be the pathophysiologic link between neuroinflammation and impairment of autophagy in PD?What may be a microglia-derived mediator that impairs autophagy and induces alpha-synuclein aggregation in dopaminergic neurons in PD?What drives neurotoxicity that could lead to oxidative stress and ROS-mediated cell loss in PD?

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“…Research continues to find expanding implications of aberrant TDP-43 protein in human diseases. TDP-43 pathology is now known to occur in more than 20 different conditions spanning neurodegenerative, developmental, trauma-related, myopathic, and even neoplastic disease categories [ 2 , 13 , 26 , 27 , 78 , 83 , 129 , 133 , 134 , 157 ]. For example, TDP-43 pathology is often seen in corticobasal degeneration, Perry syndrome, Alexander disease, and the Parkinsonism–dementia complex diseases of Guam and Kii [ 43 , 75 , 148 , 152 , 156 ].…”

Section: Differentiating Late-nc From Other Pathologiesmentioning

confidence: 99%

LATE-NC staging in routine neuropathologic diagnosis: an update

et al. 2022

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An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

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TDP‐43 Proteinopathy Presenting with Typical Symptoms of Parkinson's Disease

Abstract: Accumulation of abnormal transactivation response DNA‐binding protein of 43 kDa (TDP‐43) independently induces dopaminergic neuronal loss in the substantia nigra without Lewy pathology, and results in typical Parkinson's disease‐like motor symptoms.

Cited by 16 publications

References 7 publications

Is Tau the Initial Pathology in Dopaminergic Nigrostriatal Degeneration? Studies in Parkinsonism and Parkinson’s Disease

Is Tau the Initial Pathology in Dopaminergic Nigrostriatal Degeneration? Studies in Parkinsonism and Parkinson’s Disease

New insights underlying the early events of dopaminergic dysfunction in Parkinson’s Disease

LATE-NC staging in routine neuropathologic diagnosis: an update

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