Age-related severity of dopaminergic neurodegeneration to MPTP neurotoxicity causes motor dysfunction in C57BL/6 mice

2006 ◽  
Vol 401 (1-2) ◽  
pp. 183-187 ◽  
Author(s):  
Satoshi Ohashi ◽  
Atsushi Mori ◽  
Naoki Kurihara ◽  
Yasuhide Mitsumoto ◽  
Masami Nakai
Keyword(s):  
Motor Dysfunction ◽  
Dopaminergic Neurodegeneration ◽  
Age Related

scholarly journals Multiple genetic pathways regulating lifespan extension are neuroprotective in a G2019S LRRK2 nematode model of Parkinson’s disease

2020 ◽  
Author(s):  
Megan M. Senchuk ◽  
Jeremy M. Van Raamsdonk ◽  
Darren J. Moore
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Late Onset ◽  
Lifespan Extension ◽  
Disease Manifestation ◽  
Genetic Pathways ◽  
Dopaminergic Neurodegeneration ◽  
Age Related ◽  
Increased Risk ◽  
Extended Longevity

AbstractBackgroundMutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of late-onset, familial Parkinson’s disease (PD), and LRRK2 variants are associated with increased risk for sporadic PD. While advanced age represents the strongest risk factor for disease development, it remains unclear how different age-related pathways interact to regulate LRRK2-driven late-onset PD.FindingsIn this study, we employ a C.elegans model expressing PD-linked G2019S LRRK2 to examine the interplay between age-related pathways and LRRK2-induced dopaminergic neurodegeneration. We find that multiple genetic pathways that regulate lifespan extension can provide robust neuroprotection against mutant LRRK2. However, the level of neuroprotection does not strictly correlate with the magnitude of lifespan extension, suggesting that lifespan can be experimentally dissociated from neuroprotection. Using tissue-specific RNAi, we demonstrate that lifespan-regulating pathways, including insulin/IGF-1 signaling, TOR, and mitochondrial respiration, can be directly manipulated in neurons to mediate neuroprotection. We extend this finding for AGE-1/PI3K, where pan-neuronal versus dopaminergic neuronal restoration of AGE-1 reveals both cell-autonomous and non-cell-autonomous neuroprotective mechanisms downstream of insulin signaling.ConclusionsOur data demonstrate the importance of distinct lifespan-regulating pathways in the pathogenesis of LRRK2-linked PD, and suggest that extended longevity is broadly neuroprotective via the actions of these pathways at least in part within neurons. This study further highlights the complex interplay that occurs between cells and tissues during organismal aging and disease manifestation.

Intracerebral Neuronal Grafting in Experimental Animal Models of Age-related Motor Dysfunction

1988 ◽  
Vol 515 (1 Central Deter) ◽  
pp. 383-394 ◽  
Author(s):  
F. H. GAGE ◽  
P. BRUNDIN ◽  
R. STRECKER ◽  
S. B. DUNNETT ◽  
O. ISACSON ◽  
...  
Keyword(s):  
Animal Models ◽  
Experimental Animal ◽  
Motor Dysfunction ◽  
Experimental Animal Models ◽  
Age Related

scholarly journals Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor dysfunction and cortical atrophy, independent of protein aggregation.

2021 ◽  
Author(s):  
Haley M. Geertsma ◽  
Terry R Suk ◽  
Konrad M Ricke ◽  
Kyra Horsthuis ◽  
Jean-Louis A Parmasad ◽  
...  
Keyword(s):  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Cortical Atrophy ◽  
Nuclear Accumulation ◽  
Motor Deficits ◽  
Protein Overexpression ◽  
Dopaminergic Neurodegeneration ◽  
Disease Phenotypes ◽  
Experimental Systems ◽  
Biochemical Level

Background A growing body of evidence suggests that nuclear alpha-synuclein (aSyn) plays a role in the pathogenesis of Parkinson's disease (PD). However, this question has been difficult to address as controlling the localization of aSyn in experimental systems often requires protein overexpression, which results in aggregation. Methods We engineered SncaNLS mice which localize endogenous aSyn to the nucleus. We characterized these mice on a behavioral, histological, and biochemical level to determine whether the increase of nuclear aSyn is sufficient to elicit disease phenotypes. Results SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to aSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of SncaNLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signaling, namely Darpp-32, which we further confirmed was decreased in cortical samples of the SncaNLS mice compared to controls via immunoblotting. Conclusions These results suggest that chronic endogenous nuclear aSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of aSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis.

scholarly journals Dietary Restriction and Neuroinflammation: A Potential Mechanistic Link

2019 ◽  
Vol 20 (3) ◽  
pp. 464 ◽  
Author(s):  
Eugene Bok ◽  
Myungjin Jo ◽  
Shinrye Lee ◽  
Bo-Ram Lee ◽  
Jaekwang Kim ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Glial Cells ◽  
Dietary Restriction ◽  
Molecular Mechanisms ◽  
Motor Dysfunction ◽  
Current Understanding ◽  
Brain Disorders ◽  
Chronic Neuroinflammation ◽  
Age Related

Chronic neuroinflammation is a common feature of the aged brain, and its association with the major neurodegenerative changes involved in cognitive impairment and motor dysfunction is well established. One of the most potent antiaging interventions tested so far is dietary restriction (DR), which extends the lifespan in various organisms. Microglia and astrocytes are two major types of glial cells involved in the regulation of neuroinflammation. Accumulating evidence suggests that the age-related proinflammatory activation of astrocytes and microglia is attenuated under DR. However, the molecular mechanisms underlying DR-mediated regulation of neuroinflammation are not well understood. Here, we review the current understanding of the effects of DR on neuroinflammation and suggest an underlying mechanistic link between DR and neuroinflammation that may provide novel insights into the role of DR in aging and age-associated brain disorders.

scholarly journals Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity

2007 ◽  
Vol 12 (11) ◽  
pp. 1042-1056 ◽  
Author(s):  
E Sibille ◽  
J Su ◽  
S Leman ◽  
A M Le Guisquet ◽  
Y Ibarguen-Vargas ◽  
...  
Keyword(s):  
Early Onset ◽  
Receptor Expression ◽  
Motor Dysfunction ◽  
Age Related ◽  
Molecular Aging

scholarly journals The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance and neuronal survival in mice

2019 ◽  
Author(s):  
Adi Minis ◽  
Jose Rodriguez ◽  
Avi Levin ◽  
Kai Liu ◽  
Eve-Ellen Govek ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Time Course ◽  
Binding Protein ◽  
Critical Role ◽  
Motor Dysfunction ◽  
Neurological Dysfunction ◽  
Mouse Strains ◽  
Protein Homeostasis ◽  
Term Survival ◽  
Age Related

AbstractProteasome-mediated degradation of intracellular proteins is essential for cell function and survival. The proteasome-binding protein PI31 (Proteasomal Inhibitor of 31kD) promotes 26S assembly and functions as an adapter for proteasome transport in axons. As localized protein synthesis and degradation is especially critical in neurons, we generated a conditional loss of PI31 in spinal motor neurons (MNs) and cerebellar Purkinje cells (PCs). A cKO of PI31 in these neurons caused axon degeneration, neuronal loss and progressive spinal and cerebellar neurological dysfunction. For both MNs and PCs, markers of proteotoxic stress preceded axonal degeneration and motor dysfunction, indicating a critical role for PI31 in neuronal homeostasis. The time course of the loss of MN and PC function in developing mouse CNS suggests a key role for PI31 in human developmental neurological disorders.Statement of SignificanceThe conserved proteasome-binding protein PI31 serves as an adapter to couple proteasomes with cellular motors to mediate their transport to distal tips of neurons where protein breakdown occurs. We generated global and conditional PI31 knockout mouse strains and show that this protein is required for protein homeostasis, and that its conditional inactivation in neurons disrupts synaptic structures and long-term survival. This work establishes a critical role for PI31 and local protein degradation in the maintenance of neuronal architecture, circuitry and function. Because mutations that impair PI31 function cause neurodegenerative diseases in humans, reduced PI31 activity may contribute to age-related neurodegenerative diseases.

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