Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers

Zhao, Ye; Perera, Gayathri; Takahashi‐Fujigasaki, Junko; Mash, Deborah C.; Vonsattel, Jean Paul; Uchino, Akira; Hasegawa, Kazuko; Nichols, R. Jeremy; Holton, Janice L.; Murayama, Shigeo; Dzamko, Nicolas; Halliday, Glenda M.

doi:10.1093/brain/awx344

Cited by 42 publications

(35 citation statements)

References 37 publications

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“…Analysis of further cases, therefore, and in particular from patients with LRRK2 mutations other than the G2019S variant, will be critical to provide further resolution to the nature of the changes in autophagy in the brains of individuals with LRRK2 associated PD. In this context, it is of interest to note that LRRK2 levels are increased in early stages of iPD ( Dzamko et al, 2017 ), but are reduced in LRRK2 mutation cases ( Zhao et al, 2018 ). It is also important to note that this study analyzed the situation in the brain post mortem , and is therefore unavoidably static in nature – precluding the possibility of an examination of autophagic flux.…”

Section: Discussionmentioning

confidence: 99%

Analysis of macroautophagy related proteins in G2019S LRRK2 Parkinson’s disease brains with Lewy body pathology

Mamais

Manzoni

Nazish³

et al. 2018

Brain Research

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LRRK2, the gene encoding the multidomain kinase Leucine-Rich Repeat Kinase 2 (LRRK2), has been linked to familial and sporadic forms of Parkinson's disease (PD), as well as cancer, leprosy and Crohn's disease, establishing it as a target for discovery therapeutics. LRRK2 has been associated with a range of cellular processes, however its physiological and pathological functions remain unclear. The most prevalent LRRK2 mutations in PD have been shown to affect macroautophagy in various cellular models while a role in autophagy signalling has been recapitulated in vivo. Dysregulation of autophagy has been implicated in PD pathology, and this raises the possibility that differential autophagic activity is relevant to disease progression in PD patients carrying LRRK2 mutations. To examine the relevance of LRRK2 to the regulation of macroautophagy in a disease setting we examined the levels of autophagic markers in the basal ganglia of G2019S LRRK2 PD post-mortem tissue, in comparison to pathology-matched idiopathic PD (iPD), using immunoblotting (IB). Significantly lower levels of p62 and LAMP1 were observed in G2019S LRRK2 PD compared to iPD cases. Similarly, an increase in ULK1 was observed in iPD but was not reflected in G2019S LRRK2 PD cases. Furthermore, examination of p62 by immunohistochemistry (IH) recapitulated a distinct signature for G2019S PD. IH of LAMP1, LC3 and ULK1 broadly correlated with the IB results. Our data from a small but pathologically well-characterized cases highlights a divergence of G2019S PD carriers in terms of autophagic response in alpha-synuclein pathology affected brain regions compared to iPD.

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Section: Discussionmentioning

confidence: 99%

Analysis of macroautophagy related proteins in G2019S LRRK2 Parkinson’s disease brains with Lewy body pathology

Mamais

Manzoni

Nazish³

et al. 2018

Brain Research

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“…This increase in LRRK2 activity, however, is not found in idiopathic PD. LRRK2 is constitutively expressed in the brain, and the expression levels do not change with age or in idiopathic PD [168]. Furthermore, modest overexpression of LRRK2 alone in animal models has failed to cause selective loss of A9 neurons in the SNpc or produce robust α-syn pathology [78,84].…”

Section: Future Direction: Leucine Rich Repeat Kinase 2 (Lrrk2) and Rmentioning

confidence: 99%

Biological links between traumatic brain injury and Parkinson’s disease

Delic

Beck

Pang

et al. 2020

acta neuropathol commun

111

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Parkinson's Disease (PD) is a progressive neurodegenerative disorder with no cure. Clinical presentation is characterized by postural instability, resting tremors, and gait problems that result from progressive loss of A9 dopaminergic neurons in the substantia nigra pars compacta. Traumatic brain injury (TBI) has been implicated as a risk factor for several neurodegenerative diseases, but the strongest evidence is linked to development of PD. Mild TBI (mTBI), is the most common and is defined by minimal, if any, loss of consciousness and the absence of significant observable damage to the brain tissue. mTBI is responsible for a 56% higher risk of developing PD in U.S. Veterans and the risk increases with severity of injury. While the mounting evidence from human studies suggests a link between TBI and PD, fundamental questions as to whether TBI nucleates PD pathology or accelerates PD pathology in vulnerable populations remains unanswered. Several promising lines of research point to inflammation, metabolic dysregulation, and protein accumulation as potential mechanisms through which TBI can initiate or accelerate PD. Amyloid precursor protein (APP), alpha synuclein (α-syn), hyper-phosphorylated Tau, and TAR DNA-binding protein 43 (TDP-43), are some of the most frequently reported proteins upregulated following a TBI and are also closely linked to PD. Recently, upregulation of Leucine Rich Repeat Kinase 2 (LRRK2), has been found in the brain of mice following a TBI. Subset of Rab proteins were identified as biological substrates of LRRK2, a protein also extensively linked to late onset PD. Inhibition of LRRK2 was found to be neuroprotective in PD and TBI models. The goal of this review is to survey current literature concerning the mechanistic overlap between TBI and PD with a particular focus on inflammation, metabolic dysregulation, and aforementioned proteins. This review will also cover the application of rodent TBI models to further our understanding of the relationship between TBI and PD.

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“…VPS35 is functionally linked to LRRK2, boosting its kinase activity (Mir et al ). In fact, decreased VPS35 levels were noted in the SNpc of PD patients with LRRK2 mutations (Zhao et al ). Interestingly, over‐expression of VPS35 ameliorated locomotor deficits and enhanced lifespan in LRRK2 mutant models (MacLeod et al ; Linhart et al ), which was also seen in Parkin mutant models (Malik et al ).…”

Section: Sometimes There Are Traffic Issues: E‐l System Trafficking mentioning

confidence: 99%

Role of the endolysosomal system in Parkinson’s disease

Vidyadhara

Lee

Chandra

2019

Journal of Neurochemistry

116

105

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting 1–1.5% of the total population. While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in late stages of PD, mechanisms for early, causal pathogenic events are still elusive. Recent developments in PD genetics increasingly point at endolysosomal (E‐L) system dysfunction as the early pathomechanism and key pathway affected in PD. Clathrin‐mediated synaptic endocytosis, an integral part of the neuronal E‐L system, is probably the main early target as evident in auxilin, RME‐8, and synaptojanin‐1 mutations that cause PD. Autophagy, another important pathway in the E‐L system, is crucial in maintaining proteostasis and a healthy mitochondrial pool, especially in neurons considering their inability to divide and requirement to function an entire life‐time. PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD. Endolysosomal sorting and trafficking is also crucial, which is complex in multi‐compartmentalized neurons. VPS35 and VPS13C mutations noted in PD target these mechanisms. Mutations in GBA comprise the most common risk factor for PD and initiate pathology by compromising lysosomal function. This is also the case for ATP13A2 mutations. Interestingly, α‐synuclein and LRRK2, key proteins involved in PD, function in different steps of the E‐L pathway and target their components to induce disease pathogenesis. In this review, we discuss these E‐L system genes that are linked to PD and how their dysfunction results in PD pathogenesis. This article is part of the Special Issue “Synuclein”.

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Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers

Cited by 42 publications

References 37 publications

Analysis of macroautophagy related proteins in G2019S LRRK2 Parkinson’s disease brains with Lewy body pathology

Analysis of macroautophagy related proteins in G2019S LRRK2 Parkinson’s disease brains with Lewy body pathology

Biological links between traumatic brain injury and Parkinson’s disease

Role of the endolysosomal system in Parkinson’s disease

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