The emerging role of autophagy in Parkinson's disease

Parkinson's disease (PD) is the most common neurodegenerative movement disorder that affects about 1% of the population worldwide. Despite significant advances in the identification of genetic mutations and signaling pathways that are associated with the disease, the precise mechanisms implicated in the pathophysiology of the disease are not well understood. More importantly, treatments that are effective in reversing the progression of the disease is essentially lacking. Further investigation into the pathogenic mechanisms of PD thus presents a pressing concern for neuroscientists. Recently, deregulation of the autophagic pathway is observed in the brains of PD patients and in models of PD. In this review we summarize current literature on the emerging involvement of autophagy in PD, and the implication for future development of treatment against the disorder

Editorial: Cell and molecular signaling, and transport pathways involved in growth factor control of synaptic development and function

Since the discovery of nerve growth factor (NGF) more than a half century ago (Levi-Montalcini and Cohen, 1960), the prototypic neurotrophin family has included brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Neurotrophins bind to the Trk family of receptors, as well as the p75 receptor, to activate multiple intracellular signaling cascades (reviewed by Reichardt, 2006). BDNF receptor tropomyosin receptor kinase B (TrkB) signaling has been extensively studied for its roles in the central nervous system (CNS) ranging from cell survival, axonal and dendritic growth and synapse formation. The pathway mediates long-lasting activity-modulated synaptic changes on excitatory and inhibitory neurons and plays critical roles in circuit development and maintenance. In addition to BDNF, many studies have identified other “growth” or signaling factors in the CNS that play important roles in the development, maintenance, and control of synaptic and circuit function. However, details of the intracellular signaling systems downstream of these events are frequently unexplored. In this Research Topic, we have collected original studies and review articles that present cellular and molecular mechanisms concerning activity-dependent synapse formation and their implications for behavior and brain disorders.National Institutes of Health (U.S.) (Grant 5R01EY006039-27)National Institutes of Health (U.S.) (Grant 5R01EY014074-15

IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

Alzheimer’s disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD

Demographics and Medication Use of Patients with Late-Onset Alzheimer's Disease in Hong Kong

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly population. However, epidemiological studies on the demographics of AD in Hong Kong population are lacking. OBJECTIVE: We investigated the demographics, comorbidities, mortality rates, and medication use of patients with AD in Hong Kong to understand how the disease has been managed locally. METHODS: This was a collaborative study of The Hong Kong University of Science and Technology and the Hospital Authority Data Collaboration Lab. We analyzed the demographic data, clinical records, diagnoses, and medication records of patients with AD under the care of the Hospital Authority between January 1, 2007 and December 31, 2017. RESULTS: We identified 23,467 patients diagnosed with AD. The median age at diagnosis was 84 years old, and 71% of patients were female. The most common comorbidity was hypertension (52.6%). 39.9% of patients received medications for dementia; of those, 68.4% had taken those medications for >  1 year. Compared to nonusers, long-term AD medication users had a significantly younger age of AD onset and were taking more lipid-regulating medication, diabetes medication, or antidepressants. Surprisingly, the use of antipsychotics in patients with AD was quite common; 50.7% of patients had received any type of antipsychotic during disease progression. CONCLUSION: This study provides detailed information on the demographics and medication use of patients with AD in Hong Kong. The data from this AD cohort will aid our future research aiming to identify potential AD risk factors and associations between AD and other diseases

α-Syntrophin regulates ARMS localization at the neuromuscular junction and enhances EphA4 signaling in an ARMS-dependent manner

EphA4 signaling has recently been implicated in the regulation of synapse formation and plasticity. In this study, we show that ankyrin repeat-rich membrane spanning (ARMS; also known as a kinase D–interacting substrate of 220 kD), a substrate for ephrin and neurotrophin receptors, was expressed in developing muscle and was concentrated at the neuromuscular junction (NMJ). Using yeast two-hybrid screening, we identified a PDZ (PSD-95, Dlg, ZO-1) domain protein, α-syntrophin, as an ARMS-interacting protein in muscle. Overexpression of α-syntrophin induced ARMS clustering in a PDZ domain–dependent manner. Coexpression of ARMS enhanced EphA4 signaling, which was further augmented by the presence of α-syntrophin. Moreover, the ephrin-A1–induced tyrosine phosphorylation of EphA4 was reduced in C2C12 myotubes after the blockade of ARMS and α-syntrophin expression by RNA interference. Finally, α-syntrophin–null mice exhibited a disrupted localization of ARMS and EphA4 at the NMJ and a reduced expression of ARMS in muscle. Altogether, our findings suggest that ARMS may play an important role in regulating postsynaptic signal transduction through the syntrophin-mediated localization of receptor tyrosine kinases such as EphA4

Expression of trk in MAH Cells Lacking the p75 Low-Affinty Nerve Growth Factor Receptor is Sufficient to Permit Nerve Growth Factor-Induced Differentiation to Postmitotic Neurons

We have transfected MAH cells, an immortalized sympathoadrenal progenitor cell line, with a plasmid encoding the 140-kDa Trk protein, a nerve growth factor (NGF) receptor with protein-tyrosine kinase activity. NGF promotes neurite outgrowth and proliferation from such cells, indicating that Trk is sufficient to mediate such responses in the absence of significant levels of the endogenous 75-kDa low-affinity NGF receptor (p75). These initial NGF responses are indistinguishable from those evoked by basic fibroblast growth factor (bFGF). However, NGF is sufficient to promote terminal differentiation of a {approx}8% of trk-transfected MAH cells to postmitotic, NGF-dependent neurons, whereas all cells eventually die in medium with bFGF. Other environmental signals (such as depolarization or ciliary neurotrophic factor) can cooperate with NGF to enhance production of postmitotic NGF-dependent neurons in trk-transfected MAH cells. The terminal differentiation of sympathetic neurons thus involves sequential and cooperative actions of different growth and neurotrophic factors, as well as cell-intrinsic changes in the response to these factors

Oxaliplatin-induced loss of phosphorylated heavy neurofilament subunit neuronal immunoreactivity in rat DRG tissue

<p>Abstract</p> <p>Background</p> <p>Oxaliplatin and related chemotherapeutic drugs cause painful chronic peripheral neuropathies in cancer patients. We investigated changes in neuronal size profiles and neurofilament immunoreactivity in L5 dorsal root ganglion (DRG) tissue of adult female Wistar rats after multiple-dose treatment with oxaliplatin, cisplatin, carboplatin or paclitaxel.</p> <p>Results</p> <p>After treatment with oxaliplatin, phosphorylated neurofilament heavy subunit (pNF-H) immunoreactivity was reduced in neuronal cell bodies, but unchanged in nerve fibres, of the L5 DRG. Morphometric analysis confirmed significant changes in the number (-75%; <it>P </it>< 0.0002) and size (-45%; <it>P </it>< 0.0001) of pNF-H-immunoreactive neurons after oxaliplatin treatment. pNF-H-immunoreactive neurons had overlapping size profiles and co-localisation with neurons displaying cell body immunoreactivity for parvalbumin, non-phospho-specific neurofilament medium subunit (NF-M) and non-phospho-specific neurofilament heavy subunit (NF-H), in control DRG. However, there were no significant changes in the numbers of neurons with immunoreactivity for parvalbumin (4.6%, <it>P </it>= 0.82), NF-M (-1%, <it>P </it>= 0.96) or NF-H (0%; <it>P </it>= 0.93) after oxaliplatin treatment, although the sizes of parvalbumin (-29%, <it>P </it>= 0.047), NF-M (-11%, <it>P </it>= 0.038) and NF-H (-28%; <it>P </it>= 0.0033) immunoreactive neurons were reduced. In an independent comparison of different chemotherapeutic agents, the number of pNF-H-immunoreactive neurons was significantly altered by oxaliplatin (-77.2%; <it>P </it>< 0.0001) and cisplatin (-35.2%; <it>P </it>= 0.03) but not by carboplatin or paclitaxel, and their mean cell body area was significantly changed by oxaliplatin (-31.1%; <it>P </it>= 0.008) but not by cisplatin, carboplatin or paclitaxel.</p> <p>Conclusion</p> <p>This study has demonstrated a specific pattern of loss of pNF-H immunoreactivity in rat DRG tissue that corresponds with the relative neurotoxicity of oxaliplatin, cisplatin and carboplatin. Loss of pNF-H may be mechanistically linked to oxaliplatin-induced neuronal atrophy, and serves as a readily measureable endpoint of its neurotoxicity in the rat model.</p