Cathepsin L prevents the accumulation of alpha-synuclein fibrils in the cell.

The deposition of α-synuclein (α-Syn) fibrils in neuronal cells has been implicated as a causative factor in Parkinson's disease (PD) and dementia with Lewy Bodies (DLB). α-Syn can be degraded by autophagy, proteasome, and chaperone-mediated autophagy, and previous studies have suggested the potency of certain cathepsins, lysosomal proteases, for α-Syn degradation. However, no studies have comprehensively evaluated all cathepsins. Here, we evaluated the efficacy of all 15 cathepsins using a cell model of α-Syn fibril propagation and found that overexpression of cathepsin L (CTSL) was the most effective in preventing the accumulation of α-Syn aggregates. CTSL-mediated degradation of α-Syn aggregates was dependent on the autophagy machinery, and CTSL itself promoted autophagy flux. Interestingly, CTSL was effective in autophagic degradation of wild-type (WT) α-Syn, but not in the case of A53T and E46K missense mutations, which are causative for familial PD. These results suggest that CTSL is a potential therapeutic strategy for sporadic PD pathology in WT α-Syn.

Ventricular late potentials and myocardial fibrosis in hypertrophic cardiomyopathy.

AIMS: Ventricular late potentials (VLPs) represent delayed conduction due in part to myocardial fibrosis. We sought to examine the relationship of signal-averaged electrocardiography findings with myocardial fibrosis as assessed by cardiac magnetic resonance (CMR) in patients with hypertrophic cardiomyopathy (HCM). METHODS: This study consisted of 41 HCM patients with sinus rhythm who had undergone risk assessment including CMR and signal-averaged electrocardiography such as VLPs, filtered QRS duration, low amplitude signal duration of the terminal filtered QRS below 40 µV (LAS), and root mean square voltage of the late 40 ms of the filtered QRS (RMS). The concordance rate between VLPs and myocardial fibrosis as assessed by CMR was examined. RESULTS: Late gadolinium enhancement (LGE) on CMR was detected in 13 patients, and VLPs were detected in 14. Filtered QRS duration, LAS, RMS, and VLPs were not associated with LGE. The results of LGE and VLPs were concordant in 26 patients, whereas 15 exhibited discordance. Patients with discordance had a higher maximum wall thickness (24.1 ±â€¯4.0 mm versus 21.0 ±â€¯5.9 mm, p < 0.05), higher LGE volume (2.3 ±â€¯1.2 g/cm versus 0.0 ±â€¯0.8 g/cm, p < 0.01), lower LGE volume/the total number of sites with LGE (1.5 ±â€¯0.7 versus 3.1 ±â€¯2.8, p < 0.01), and predominant LGE location of the interventricular septum and anterior wall (60% versus 8%, p < 0.01) than patients with concordance. CONCLUSION: VLPs were not a reliable marker for the detection of myocardial fibrosis as assessed by LGE on CMR in our cohort of patients with HCM. CONDENSED ABSTRACT: Ventricular late potentials on signal-averaged electrocardiography represent delayed conduction due in part to myocardial fibrosis but were not an alternative to cardiac magnetic resonance for detecting myocardial fibrosis in patients with hypertrophic cardiomyopathy.