Saposin C, Key Regulator in the Alpha-Synuclein Degradation Mediated by Lysosome.

Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for the lysosomal enzyme ß-glucocerebrosidase (ß-GCase), considered the main genetic risk factor for sporadic PD. The loss of ß-GCase activity results in the formation of α-synuclein deposits. The present study was aimed to determine the activity of the main lysosomal enzymes and the cofactors Prosaposin (PSAP) and Saposin C in PD and healthy controls, and their contribution to α-synuclein (α-Syn) aggregation. 42 PD patients and 37 age-matched healthy controls were included in the study. We first analyzed the ß-GCase, ß-galactosidase (ß-gal), ß-hexosaminidase (Hex B) and Cathepsin D (CatD) activities in white blood cells. We also measured the GBA, ß-GAL, ß-HEX, CTSD, PSAP, Saposin C and α-Syn protein levels by Western-blot. We found a 20% reduced ß-GCase and ß-gal activities in PD patients compared to controls. PSAP and Saposin C protein levels were significantly lower in PD patients and correlated with increased levels of α-synuclein. CatD, in contrast, showed significantly increased activity and protein levels in PD patients compared to controls. Increased CTSD protein levels in PD patients correlated, intriguingly, with a higher concentration of α-Syn. Our findings suggest that lysosomal dysfunction in sporadic PD is due, at least in part, to an alteration in Saposin C derived from reduced PSAP levels. That would lead to a significant decrease in the ß-GCase activity, resulting in the accumulation of α-syn. The accumulation of monohexosylceramides might act in favor of CTSD activation and, therefore, increase its enzymatic activity. The evaluation of lysosomal activity in the peripheral blood of patients is expected to be a promising approach to investigate pathological mechanisms and novel therapies aimed to restore the lysosomal function in sporadic PD.

Neurophysiological study in cerebrotendinous xanthomatosis.

INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal-recessive disease due to mutations of the 27α-hydroxylase. It is characterized by cataracts, xanthomas, and neurological manifestations. Polyneuropathy has been reported, although it is unclear whether it is axonal or demyelinating. METHODS: We report clinical and neurophysiological results of 13 patients with CTX diagnosed in Spain. RESULTS: In 8 patients (62%), peripheral neuropathy was demonstrated (4 demyelinating, 3 axonal, and 1 mixed; 3 predominantly motor and 5 sensorimotor). All patients had clinical signs/symptoms of peripheral neuropathy. Upper limb somatosensory evoked potentials (SSEPs) were affected in 38% of patients, and lower limb SSEPs in 67%. Fifty percent of patients had delayed brainstem auditory evoked potentials, and 43% had affected visual evoked potentials. DISCUSSION: In this series, polyneuropathy was predominantly sensorimotor and demyelinating. Neurophysiological studies correlated only partially with clinical follow-up. Therefore, we recommend neurophysiological follow-up studies only if clinical symptoms are present.

Oxidative stress and aminopeptidases in Parkinson's disease patients with and without treatment.

BACKGROUND/OBJECTIVE: Mitochondrial dysfunction, oxidative stress and protein metabolism impairment are the main molecular events underlying the pathogenesis of Parkinson's disease (PD). However, only few studies have addressed the changes produced by these phenomena in the blood of PD patients. Our purpose was to compare oxidative stress between newly diagnosed PD patients (ntPD) and PD patients under treatment (tPD). We also analyzed changes in plasma activity of several aminopeptidases (AP) involved in the metabolism of various active peptides. METHODS: Plasma lipid peroxide (LPO) and lactate (LAC) concentrations were measured by colorimetric methods, and plasma AP activities were determined by fluorometric assay. RESULTS: LPO and LAC concentrations were significantly elevated in ntPD and tPD patients versus controls, but there were no differences between the PD groups. Alanine-, cystine- and aspartate-AP activities were significantly lower in tPD versus ntPD patients. Nondenaturing electrophoresis and Western blot results confirmed these findings. CONCLUSIONS: The plasma LPO and LAC levels were high in both PD groups, indicating that they are elevated at an early stage of PD and are not affected by anti-PD treatment. The higher AP activities in ntPD versus tPD patients suggest that anti-PD treatment may improve protein metabolism while not altering oxidative stress. A therapy directed to reduce oxidative stress and normalize AP activity may be useful in the treatment of PD.

Re-evaluating the accuracy of optimized electrodiagnostic criteria in very early Guillain-Barré syndrome: a sequential study.

Using recent optimized electrodiagnostic criteria sets, we aimed at verifying the accuracy of initial nerve conduction studies (NCS) in classic very early Guillain-Barré syndrome (VEGBS), ≤ 4 days after onset, compared with the results of serial NCS. This is a retrospective study based on unreported and consecutive VEGBS patients admitted to two university hospitals between 2015 and 2019. Each patient had serial NCS in at least four nerves. Initial NCS studies were done within 4 days after onset, and serial ones from days 20 to 94. Electrophysiological recordings were blinded evaluated by four of the authors, GBS subtype being established accordingly. Seven adult classic VEGBS patients were identified with a median age of 58 years. At first NCS, GBS subtyping was only possible in 1 case that exhibited an axonal pattern, the remaining patterns being equivocal in 3, and mixed (combining axonal and demyelinating criteria) in the remaining 3. Upon serial NSC there was a rather intricate evolution of electrophysiological GBS patterns, 3 of them being classified as axonal or demyelinating, and the remaining 4 as equivocal or mixed. NCS in VEGBS systematically allows detection of changes suggestive of peripheral neuropathy, though even after serial studies accurate GBS subtyping was only possible in 43% of cases. We provide new pathophysiological insights for better understanding of the observed electrophysiological changes.

Plasma alpha-synuclein in patients with Parkinson's disease with and without treatment.

Alpha-synuclein (alpha-syn) is an intracellular protein with a high tendency to aggregation. It is the major component of Lewy bodies and may play a key role in the pathogenesis of Parkinson's disease (PD). alpha-Syn is also released by neurons and can be detected in biological fluids, such as plasma. The purpose of this study was to determine whether plasma alpha-syn concentrations are elevated in newly diagnosed PD patients before treatment (nontreated PD group, ntPD; n = 53) and to compare them with concentrations in PD patients with at least 1 year of specific treatment (tPD; n = 42) and in healthy controls (n = 60). Plasma alpha-syn concentrations in the ntPD and tPD groups were similar and significantly higher than in healthy controls. In conclusion, alpha-syn was elevated early in the development of PD and specific PD treatment did not change plasma alpha-syn levels.

Oxidative stress and plasma aminopeptidase activity in Huntington's disease.

Huntington's disease (HD) is a genetic neurodegenerative disorder. Oxidative stress, mitochondrial dysfunction, and protein metabolism impairment have been implicated in its pathogenesis. However, the contribution of these phenomena to HD onset or progression is not well known, and they have been less studied in peripheral blood. We analyzed plasma lipid peroxide (LPO) and lactate (LAC) concentrations as indicators of oxidative stress and mitochondrial dysfunction in symptomatic HD patients (sHD) and asymptomatic HD gene carriers (aHD). We also measured the plasma activity of aminopeptidases (APs), an important group of proteolytic enzymes. LPO and LAC concentrations were significantly elevated in sHD patients but not in aHD carriers. Aspartate and glutamate AP activities were significantly reduced in sHD patients and aHD carriers. These findings demonstrate that sHD patients are under oxidative stress, which may favor progression of the disease. Plasma AP activity was decreased before the appearance of HD symptoms and oxidative stress and may be related to protein metabolism impairment. These results indicate that therapy directed to improve oxidative stress and normalize AP activity may be useful in the treatment of HD. They also suggest that decreased plasma AP activity in aHD carriers may predict the future onset of HD symptoms.

Structural genomic variations and Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease, whose prevalence is projected to be between 8.7 and 9.3 million by 2030. Until about 20 years ago, PD was considered to be the textbook example of a "non-genetic" disorder. Nowadays, PD is generally considered a multifactorial disorder that arises from the combination and complex interaction of genes and environmental factors. To date, a total of 7 genes including SNCA, LRRK2, PARK2, DJ-1, PINK 1, VPS35 and ATP13A2 have been seen to cause unequivocally Mendelian PD. Also, variants with incomplete penetrance in the genes LRRK2 and GBA are considered to be strong risk factors for PD worldwide. Although genetic studies have provided valuable insights into the pathogenic mechanisms underlying PD, the role of structural variation in PD has been understudied in comparison with other genomic variations. Structural genomic variations might substantially account for such genetic substrates yet to be discovered. The present review aims to provide an overview of the structural genomic variants implicated in the pathogenesis of PD.