Macroautophagy is a cellular mechanism for the clearance of protein aggregates and damaged organelles. Impaired macroautophagy has been observed in neurodegenerative disorders. We investigated the ...macroautophagy pathway in essential tremor (ET) cases compared to age-matched controls. We analyzed microtubule-associated protein light chain 3-II (LC3-II), S6K, phosphorylated S6K, beclin-1, and mitochondrial membrane proteins levels by Western blot in the post-mortem cerebellum of 10 ET cases and 11 controls. We also performed immunohistochemistry in 12 ET cases and 13 controls to quantify LC3 clustering in Purkinje cells (PCs). LC3-II protein levels were significantly lower in ET cases vs. controls on Western blot (0.84 ± 0.14 vs. 1.00 ± 0.14, p = 0.02), and LC3-II clustering in PCs by immunohistochemistry was significantly lower in ET cases vs. controls (2.03 ± 3.45 vs. 8.80 ± 9.81, p = 0.03). In ET cases, disease duration was inversely correlated with LC3-II protein level (r = -0.64, p = 0.046). We found that mitochondrial membrane proteins were accumulated in ET (TIM23: 1.36 ± 0.11 in ET cases vs. 1.00 ± 0.08 in controls, p = 0.02; TOMM20: 1.63 ± 0.87 in ET cases vs. 1.00 ± 0.14 in controls, p = 0.03). Beclin-1, which is involved in macroautophagy, was strikingly deficient in ET (0.42 ± 0.13 vs. 1.00 ± 0.35, p<0.001). Decreased macroautophagy was observed in the ET cerebellum, and this could be due to a decrease in beclin-1 levels, which subsequently lead to mitochondrial accumulation as a result of autophagic failure. This provides a possible means by which perturbed macroautophagy could contribute to PC pathology in ET.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. We found LRRK2 to be degraded in lysosomes by chaperone-mediated autophagy (CMA), whereas ...the most common pathogenic mutant form of LRRK2, G2019S, was poorly degraded by this pathway. In contrast to the behavior of typical CMA substrates, lysosomal binding of both wild-type and several pathogenic mutant LRRK2 proteins was enhanced in the presence of other CMA substrates, which interfered with the organization of the CMA translocation complex, resulting in defective CMA. Cells responded to such LRRK2-mediated CMA compromise by increasing levels of the CMA lysosomal receptor, as seen in neuronal cultures and brains of LRRK2 transgenic mice, induced pluripotent stem cell-derived dopaminergic neurons and brains of Parkinson's disease patients with LRRK2 mutations. This newly described LRRK2 self-perpetuating inhibitory effect on CMA could underlie toxicity in Parkinson's disease by compromising the degradation of α-synuclein, another Parkinson's disease-related protein degraded by this pathway.
ABSTRACTFor many years, clinicians have commented on the development ofsigns of parkinsonism among their essential tremor (ET) patients, but the links between ET and parkinsonism are not well ...understood. We report 11 (12.4%) of 89 ET patients who were prospectively collected at the Essential Tremor Centralized Brain Repository during the course of its first 9 years. All patients had long-standing ET (median duration, 38 years); there was a 5- to 49-year latency from the onset of ET to the development of either parkinsonism or dementia.Despite the presence of parkinsonism or dementia during life, none had been diagnosed clinically with progressive supranuclear palsy(PSP). All 11 received the postmortem diagnosis of PSP. The prevalence of PSP in this ET sample (12.4%) is clearly larger than the population prevalence of PSP (0.001%–0.0065%). Itis also 2 to 5 times the proportion of normal cases with incidental PSP in 2 previous autopsy series. This case series raises the questions of an association between ET and PSP, whether ET patients are at anincreased risk of developing PSP, and what the proportion of ETpatients who develop presumed Parkinson disease or Alzheimer disease in life actually have PSP (i.e. ET + PSP).
PPP2R5D‐related neurodevelopmental disorder is characterized by a range of neurodevelopmental and behavioral manifestations. We report the association of early‐onset parkinsonism with the PPP2R5D ...p.E200K mutation. Clinical characterization and exome sequencing were performed on three patients, with postmortem neuropathologic examination for one patient. All patients had mild developmental delay and developed levodopa‐responsive parkinsonism between the ages of 25 and 40 years. The PPP2R5D c.598G>A (p.E200K) mutation was identified in all patients. Neuropathologic examination demonstrated uneven, focally severe neuronal loss and gliosis in the substantia nigra pars compacta, without Lewy bodies. Our findings suggest the PPP2R5D p.E200K mutation to be a possible new cause of early‐onset parkinsonism. ANN NEUROL 2020;88:1028–1033
•Clinically, LRRK2 Parkinson's disease (PD) may be indistinguishable from idiopathic PD.•Neuronal loss in the substantia nigra pars compacta (SNpc) and α-synuclein containing Lewy bodies are ...pathologic criteria for PD..•We present a case of LRRK2-PD with clinical diagnosis of PD but no α-synuclein deposits in the SNpc.
Whether or how the pathogenic disruptions in endosomal trafficking observed in Alzheimer’s disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these ...questions by showing that neurons are enriched with a second retromer core, organized around VPS26b, differentially dedicated to endosomal recycling. Next, by imaging mouse models, we show that the trans-entorhinal cortex, a region most vulnerable to AD, is most susceptible to VPS26b depletion—a finding validated by electrophysiology, immunocytochemistry, and behavior. VPS26b was then found enriched in the trans-entorhinal cortex of human brains, where both VPS26b and the retromer-related receptor SORL1 were found deficient in AD. Finally, by regulating glutamate receptor and SORL1 recycling, we show that VPS26b can mediate regionally selective synaptic dysfunction and SORL1 deficiency. Together with the trans-entorhinal’s unique network properties, hypothesized to impose a heavy demand on endosomal recycling, these results suggest a general mechanism that can explain AD’s regional vulnerability.
Display omitted
•Neurons are endowed with a separate VPS26b-retromer dedicated to endosomal recycling•The trans-entorhinal cortex (TEC) differentially depends on VPS26b-retromer•VPS26b in mice regulates entorhinal-based memory, LTP, and SORL1 recycling•VPS26b is enriched in the human TEC, whereas VPS26b and SORL1 are deficient in AD
Trans-entorhinal cortex neurons are most vulnerable to Alzheimer’s disease. Simoes et al. explain this vulnerability by showing that these neurons are dependent on a distinct VPS26b-retromer core differentially dedicated to endosomal recycling. VPS26b is highly expressed in these neurons, where they regulate synaptic function, GluA1/SORL1 recycling, and disease-associated pathologies
PDF
