Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases.

Lysosomes are the main organelles responsible for the degradation of macromolecules in eukaryotic cells. Beyond their fundamental role in degradation, lysosomes are involved in different physiological processes such as autophagy, nutrient sensing, and intracellular signaling. In some circumstances, lysosomal abnormalities underlie several human pathologies with different etiologies known as known as lysosomal storage disorders (LSDs). These disorders can result from deficiencies in primary lysosomal enzymes, dysfunction of lysosomal enzyme activators, alterations in modifiers that impact lysosomal function, or changes in membrane-associated proteins, among other factors. The clinical phenotype observed in affected patients hinges on the type and location of the accumulating substrate, influenced by genetic mutations and residual enzyme activity. In this context, the scientific community is dedicated to exploring potential therapeutic approaches, striving not only to extend lifespan but also to enhance the overall quality of life for individuals afflicted with LSDs. This review provides insights into lysosomal dysfunction from a molecular perspective, particularly in the context of human diseases, and highlights recent advancements and breakthroughs in this field.

Ambra1 haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration.

Macroautophagy/autophagy is a key process in the maintenance of cellular homeostasis. The age-dependent decline in retinal autophagy has been associated with photoreceptor degeneration. Retinal dysfunction can also result from damage to the retinal pigment epithelium (RPE), as the RPE-retina constitutes an important metabolic ecosystem that must be finely tuned to preserve visual function. While studies of mice lacking essential autophagy genes have revealed a predisposition to retinal degeneration, the consequences of a moderate reduction in autophagy, similar to that which occurs during physiological aging, remain unclear. Here, we described a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene. These mice showed protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, Ambra1+/gt mice were more prone to retinal degeneration after RPE stress. These findings indicate that autophagy provides crucial support to RPE-retinal metabolism and protects the retina against stress and physiological aging.Abbreviations : 4-HNE: 4-hydroxynonenal; AMBRA1: autophagy and beclin 1 regulator 1, AMD: age-related macular degeneration;; GCL: ganglion cell layer; GFAP: glial fibrillary acidic protein; GLUL: glutamine synthetase/glutamate-ammonia ligase; HCL: hierarchical clustering; INL: inner nuclear layer; IPL: inner plexiform layer; LC/GC-MS: liquid chromatography/gas chromatography-mass spectrometry; MA: middle-aged; MTDR: MitoTracker Deep Red; MFI: mean fluorescence intensity; NL: NH4Cl and leupeptin; Nqo: NAD(P)H quinone dehydrogenase; ONL: outer nuclear layer; OPL: outer plexiform layer; OP: oscillatory potentials; OXPHOS: oxidative phosphorylation; PCR: polymerase chain reaction; PRKC/PKCα: protein kinase C; POS: photoreceptor outer segment; RGC: retinal ganglion cells; RPE: retinal pigment epithelium; SI: sodium iodate; TCA: tricarboxylic acid.

Role of Inflammatory Cytokines in the Conversion of Mild Cognitive Impairment to Dementia: A Prospective Study.

BACKGROUND: The effect that cytokines can exert on the progression from mild cognitive impairment (MCI) to ongoing dementia is a matter of debate and the results obtained so far are controversial. OBJECTIVE: The aim of the study is to analyze the influence of markers of subclinical inflammation on the progression of MCI to dementia. METHODS: A prospective study involving a cohort of patients ≥ 65 years of age diagnosed with MCI and followed for 3 years was conducted. 105 patients were enrolled, and serum concentrations of several subclinical inflammatory markers were determined. RESULTS: After 3.09 (2 - 3.79) years of follow-up, 47 (44.76%) patients progressed to dementia. Alpha 1-antichymotrypsin (ACT) was found to be significantly higher in patients who progressed to dementia (486.45 ± 169.18 vs. 400.91 ± 163.03; p = 0.012), and observed to significantly increase the risk of developing dementia in patients with mild cognitive impairment (1.004, 1.001-1.007; p = 0.007). IL-10 levels were significantly higher in those who remained stable (6.69 ± 18.1 vs. 32.54 ± 89.6; p = 0.04). Regarding the type of dementia to which our patients progressed, we found that patients who developed mixed dementia had higher IL-4 levels than those who converted to AD (31.54 ± 63.6 vs. 4.43 ± 12.9; p = 0.03). No significant differences were observed between the groups with regard to the ESR and LPa, CRP, IL-1 and TNF-α levels. CONCLUSION: ACT levels have a significant predictive value in the conversion of MCI to dementia. IL-10 levels could be a protective factor. It is necessary to conduct studies with serial determinations of these and other inflammatory markers in order to determine their effect on the progression of MCI to dementia.

Vascular Risk Factors and Lesions of Vascular Nature in Magnetic Resonance as Predictors of Progression to Dementia in Patients with Mild Cognitive Impairment.

BACKGROUND: Evidence of the effect of vascular risk factors and white matter lesions on the progression of mild cognitive impairment (MCI) to dementia is not conclusive. OBJECTIVE: The study aimed to analyze the impact of these factors on MCI progression to dementia from a global perspective. METHODS: Our study included a population of 105 patients with MCI. RESULTS: After a mean follow-up period of 3.09 years (range, 2-3.79), 47 patients (44.76%) progressed to dementia: 32 (30.8%) to mixed dementia, 13 (12.5%) to probable AD, and 2 (1.9%) to vascular dementia. Total cholesterol levels (OR: 1.015 [1.003-1.028]) and LDL cholesterol levels (OR: 1.018 [1.004-1.032]) increased the risk of progression to dementia. Cystatin C was a protective factor against progression to dementia (OR: 0.119 [0.015-0.944], p = 0.044). During the second year of follow-up, the presence of subcortical white matter hyperintensities increased the risk of progression to dementia (OR: 5.854 [1.008- 33.846]). Subcortical and periventricular white matter hyperintensities were also associated with an increased risk of progression to dementia during the second year of follow-up (OR: 3.130 [1.098-8.922] and OR: 3.561 [1.227-10.334], respectively). The same was true for silent infarcts (OR: 4.308 [1.480- 12.500]). CONCLUSION: A high percentage of patients progressed to dementia. Total cholesterol, LDL cholesterol, and white matter hyperintensities were found to be associated with MCI progression to dementia. In contrast, cystatin C was shown to be a protective factor against progression to dementia.

Association of vascular factors and amnestic mild cognitive impairment: a comprehensive approach.

BACKGROUND AND OBJECTIVE: Current evidence shows that numerous classic vascular risk factors (VRF) contribute to mild cognitive impairment (MCI), but the effects of emerging VRFs are less well-known. Using a comprehensive approach, we assessed the frequency and strength of association between MCI and classic VRFs, subclinical markers of atherosclerosis (cystatin C, lipoprotein(a), high-sensitivity C-reactive protein, and intima-media thickness) and white matter hyperintensities (WMH). METHODS: In this case-control study of consecutive MCI patients and cognitively normal controls, subjects underwent clinical and neuropsychological examinations, laboratory analyses, a carotid duplex scan, and a brain magnetic resonance imaging scan. RESULTS: The study included 105 patients with amnestic MCI (aMCI): 24 with single domain amnestic MCI, 81 with multiple domain amnestic MCI, and 76 controls. Compared to controls, patients with aMCI were significantly older and had higher rates of arterial hypertension, atrial fibrillation, and depression. They also had a larger intima-media thickness and higher load of WMHs, both periventricular (WMHpv) and subcortical (WMHsc). In the adjusted analysis, all variables except WMHsc displayed a significant association with aMCI. Body mass index exerted a protective effect. CONCLUSIONS: Our findings suggest a direct association between aMCI and age, hypertension, atrial fibrillation depression, intima-media thickness, and WMHpv. Body mass index has a protective effect on this MCI subtype.