Junsheng Yang

Autophagy impairment in Huntington disease (HD) has been reported for almost two decades. However, the molecular mechanisms underlying this phenomenon are still unclear. This is partially because it is challenging to model the impact of the disease‐causing mutation, aging, as well as the selective vulnerability of neurons in a single model. Recently developed direct neuronal reprogramming that allows researchers to induce neurons‐of‐interest retaining biological aging information made it possible to establish HD cellular models to study more relevant age‐ and disease‐related molecular changes in neurons. We here summarized the findings from a few latest studies utilizing directly reprogrammed HD neurons and discussed the new insights they brought to the understanding of the age‐ and disease‐related autophagy impairment in HD.

To evaluate the possibility of judging the degree of bone healing by wall thickness analysis provide reference for quantitative analysis of bone healing. Patients with lower limb fracture from April 2014 to October 2019 were recruited and divided into bone healing (group A), poor bone healing (group B), and nonunion (group C). Models were built in Mimics 20.0 with DICOM 3.0 data obtained from patient’s CT. Three-dimensional geometric models of unaffected limb and affected limb after simulated removal of internal fixation were established, corresponding to basic phase and simulated phase, respectively. Wall thickness analysis was performed to obtain median wall thickness after meshing. R2 (median wall thickness ratio), R4 (CT value ratio), and R5 (healing index ratio) were obtained by calculating the ratio of each value in simulated phase to that in basic phase. Receiver operating characteristic curve analysis was used to evaluate the ability of Wall Thickness Analysis to indicate fracture healing. 112 CT scans of 79 patients were included in the study. The frequency of categorization in groups A, B, and C was 49, 37 and 26, respectively. The median R2 in groups A, B, and C was 0.91, 0.80, and 0.67, respectively (group A > group B > group C, all P < 0.05). The best cutoff point for R2 in predicting bone healing was 0.84, and predicting bone nonunion was 0.74. The Wall Thickness Analysis can be used to quantitatively evaluate fracture healing state, with median wall thickness ratio as a more intuitive and reliable judgment index.

The autophagy-lysosomal pathway (ALP) is the major biological pathway responsible for clearing intracellular protein aggregates, therefore a promising target for treating diseases featuring the accumulation of aggregation-prone proteins, such as Huntington disease (HD). However, accumulating evidence indicated that targeting ALP to treat HD is pharmacologically challenging due to the complexity of autophagy and the autophagy defects in HD cells. Here in this mini-review, we summarized the current challenges in targeting ALP in HD and discussed a number of latest findings on aggrephagy and targeted protein degradation, which we believe will provide potential new targets and new strategies for treating HD via ALP.

The aggregation of mutant HTT (huntingtin; mHTT) is a hallmark of Huntington disease (HD). mHTT aggregates interact and sequester dozens of proteins and affect diverse key cellular functions. Here we report that TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, is yet another protein that co-aggregates with mHTT. We also found the mHTT-TFEB co-aggregation is mediated by a prion-like domain (PrLD) near the N terminus of TFEB. Our findings point out a possible limitation for therapeutic strategies targeting TFEB to clear mHTT, and also provided a possible explanation for controversies that TFEB overexpression lowered soluble mHTT in some HD models but failed to reduce mHTT aggregates or HD pathology in others. Moreover, we found that TFE3, another MiT family transcription factor that shares overlapping functions with TFEB, lacks PrLD and does not co-aggregate with mHTT, and thus might serve as an alternative drug target for HD.

Huntington disease (HD) manifests a unique macroautophagy/autophagy defect: the presense of cytosolic autophagosomes without substrates or so-called “empty” autophagosomes. It was proposed that mutant HTT (huntingtin; mHTT) disrupts cargo recognition by the selective autophagy receptor SQSTM1/p62 thus leading to the failure of cargo sequestration by phagophores, the precursors to autophagosomes. Here we looked at recent discoveries that liquid-like SQSTM1 droplets can serve as platforms for autophagosome formation, and discussed possible alternative mechanisms for “empty” autophagosome formation in HD inspired by these findings.

Formation of intracellular mutant Huntingtin (mHtt) aggregates is a hallmark of Huntington’s disease (HD). The mechanisms underlying mHtt aggregation, however, are still not fully understood. A few recent studies indicated mHtt undergoes phase transition, bringing new clues to understand how mHtt aggregates assemble. Here in this mini review, we will summarize these findings with a focus on the factors that affect mHtt phase transition. We will also discuss the possible pathological roles of mHtt phase separation in HD.

Rapamycin (Rap) and its derivatives, called rapalogs, are being explored in clinical trials targeting cancer and neurodegeneration. The underlying mechanisms of Rap actions, however, are not well understood. Mechanistic target of rapamycin (mTOR), a lysosome-localized protein kinase that acts as a critical regulator of cellular growth, is believed to mediate most Rap actions. Here, we identified mucolipin 1 (transient receptor potential channel mucolipin 1 [TRPML1], also known as MCOLN1), the principle Ca²⁺ release channel in the lysosome, as another direct target of Rap. Patch-clamping of isolated lysosomal membranes showed that micromolar concentrations of Rap and some rapalogs activated lysosomal TRPML1 directly and specifically. Pharmacological inhibition or genetic inactivation of mTOR failed to mimic the Rap effect. In vitro binding assays revealed that Rap bound directly to purified TRPML1 proteins with a micromolar affinity. In both healthy and disease human fibroblasts, Rap and rapalogs induced autophagic flux via nuclear translocation of transcription factor EB (TFEB). However, such effects were abolished in TRPML1-deficient cells or by TRPML1 inhibitors. Hence, Rap and rapalogs promote autophagy via a TRPML1-dependent mechanism. Given the demonstrated roles of TRPML1 and TFEB in cellular clearance, we propose that lysosomal TRPML1 may contribute a significant portion to the in vivo neuroprotective and anti-aging effects of Rap via an augmentation of autophagy and lysosomal biogenesis.

Lysosomes are central organelles that recycle materials and energy to maintain intracellular homeostasis. Lysosomes are capable of sensing environmental cues such as nutrition to regulate their function accordingly. Whether lysosomes can sense redox signaling, however, was unclear. Here in this review, we summarized recent evidence of lysosomal ion channel as redox sensors for this organelle. We also discussed their roles in lysosomal diseases that features imbalanced redox.

Background & Objective: Increased level of reactive oxygen species is a hallmark of common neurodegenerative diseases such as Alzheimer’s Disease and Parkinson’s Disease. ROS can oxidize macromolecules including DNA, lipids and proteins and cause oxidative damage to the cell. Emerging evidence indicate that potassium channels in the central nervous system are no exceptions to these oxidative modifications. Conclusion: In this mini-review, we summarized recent reports on the oxidation of potassium channels in the CNS and the consequently resulted changes in cell functions and viability, with focus on its implications in neurodegenerative diseases.