Influence of microRNA deregulation on chaperone-mediated autophagy and α-synuclein pathology in Parkinson's disease

The presence of α-synuclein aggregates in the characteristic Lewy body pathology seen in idiopathic Parkinson's disease (PD), together with α-synuclein gene mutations in familial PD, places α-synuclein at the center of PD pathogenesis. Decreased levels of the chaperone-mediated autophagy (CMA) proteins LAMP-2A and hsc70 in PD brain samples suggests compromised α-synuclein degradation by CMA may underpin the Lewy body pathology. Decreased CMA protein levels were not secondary to the various pathological changes associated with PD, including mitochondrial respiratory chain dysfunction, increased oxidative stress and proteasomal inhibition. However, decreased hsc70 and LAMP-2A protein levels in PD brains were associated with decreases in their respective mRNA levels. MicroRNA (miRNA) deregulation has been reported in PD brains and we have identified eight miRNAs predicted to regulate LAMP-2A or hsc70 expression that were reported to be increased in PD. Using a luciferase reporter assay in SH-SY5Y cells, four and three of these miRNAs significantly decreased luciferase activity expressed upstream of the lamp-2a and hsc70 3'UTR sequences respectively. We confirmed that transfection of these miRNAs also decreased endogenous LAMP-2A and hsc70 protein levels respectively and resulted in significant α-synuclein accumulation. The analysis of PD brains confirmed that six and two of these miRNAs were significantly increased in substantia nigra compacta and amygdala respectively. These data support the hypothesis that decreased CMA caused by miRNA-induced downregulation of CMA proteins plays an important role in the α-synuclein pathology associated with PD, and opens up a new avenue to investigate PD pathogenesis

Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency

Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how the combined deficiencies of both enzymes might interact to modulate PD has yet to be explored. Therefore, we created a double-knockout (DKO) zebrafish line for both gba1 (or gba) and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO line compared to those for single mutants. Unexpectedly, DKO zebrafish maintained conventional swimming behaviour and had normalised neuronal gene expression signatures compared to those of single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKO zebrafish. Despite having an unexpected rescue effect, our results confirm ASM as a modifier of GBA1 deficiency in vivo. Our study highlights the need for validating how genetic variants and enzymatic deficiencies may interact in vivo

Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

Objectives:To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.Methods:A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated.Results:Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). The asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations.Conclusions:The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss

Bimodalne stosowanie entakaponu u pacjentów z chorobą Parkinsona

Zahamowanie katecholo-tleno-metylotransferazy (COMT, catechol- O-methyl transferase) przez entakapon prowadzi do zwiększenia wchłaniania lewodopy oraz skrócenia okresu wyłączenia (off) w chorobie Parkinsona (PD, Parkinson’s disease). Autorzy wysunęli hipotezę, że entakapon podany bimodalnie (2 dawki w odstępie 1 h) mógłby zwiększać wchłanianie lewodopy oraz wpływać na poprawę kontroli ruchowej u pacjentów z PD. Preparaty lewodopy o szybkim (IR, immediate release) i kontrolowanym (CR, controlled release) uwalnianiu podawano pacjentom z PD (n=17) łącznie z jedną lub dwoma dawkami entakaponu. Bimodalny sposób podania entakaponu prowadził do istotnego wydłużenia okresu półtrwania lewodopy IR i CR, zwiększenia pola pod krzywą (AUC, area under the curve) oraz Cmaks. po zastosowaniu preparatu lewodopy CR. Bimodalne podanie entakaponu w połączeniu z preparatami lewodopy, zarówno IR, jak i CR, powodowało istotną poprawę sprawności ocenianej według III części ujednoliconej skali oceny PD (UPDRS, Unified Parkinson’s Disease Rating Scale). Bimodalne podanie entakaponu w większym stopniu blokowało COMT, wpływało korzystnie na farmakokinetykę lewodopy oraz punktową ocenę stanu sprawności motorycznej w okresie 6-8 godzin. Taki sposób podawania entakaponu może wpływać na poprawę kontroli sprawności ruchowej u wybranych pacjentów, co oznaczałoby, że kontrola hamowania COMT jest korzystna u osób z PD