Limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM) are autosomal recessive disorders caused by mutations in the dysferlin gene on chromosome 2p13. The authors studied a large Russian family with both LGMD2B and MM. All affected individuals, as well as one preclinical boy with dystrophic changes on muscle biopsy, were found to be homozygous for a novel dysferlin mutation, TG573/574AT (Val67Asp). This finding supports the view that additional factors (e.g., modifier genes) contribute to the phenotypic expression of causative mutations in dysferlinopathies.

We describe a unique six-generation, highly consanguineous family originating from an isolated mountainous village in the Russian province of Daghestan. Three separate clinical phenotypes of progressive muscular dystrophy were identified in this large family. Seven patients developed a classical limb-girdle variant of muscular dystrophy (LGMD), with disease onset at 15–30 years and loss of ambulation within a 25-year course. The second group included three patients with a slowly progressive distal myopathy first manifested in the late teens and confined to the tibial and calf muscles. Each of these two phenotypes segregated independently as an autosomal recessive trait, and muscle biopsies showed non-specific myopathic changes. Lastly, two male siblings exhibited an atypical variant of Duchenne muscular dystrophy confirmed by detection of a deletion in the dystrophin gene. To clarify the molecular basis of the polymorphic autosomal recessive form of muscular dystrophy in this kindred, we performed molecular genetic studies on 67 family members and obtained significant evidence for linkage to chromosome 2p. A maximum pairwise lod (logarithm of odds) score of 5.64 was achieved at the zero recombination fraction (i.e. at θ = 0.00) for locus D2S291; multipoint linkage analysis confirmed the most likely location of a mutant gene near D2S291. The patients with LGMD and those with the distal muscular dystrophy phenotype share a common affected homozygous haplotype associated with the same founder chromosome; key recombinants defined D2S286 and D2S292 to be the closest loci flanking the mutant gene. Remarkably, two clinically distinct forms of autosomal recessive muscular dystrophy, LGMD type 2B (LGMD2B) and Miyoshi myopathy, were recently mapped to the same locus. We suggest that all three chromosome 2p-linked conditions may represent allelic disorders, i.e. different phenotypic expressions of a single gene.

Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become evident that at the cellular level, various hallmarks of an aging brain are closely related to mitophagy. The importance of mitochondria quality and quantity control through mitophagy is highlighted by the contribution that defects in mitochondria–autophagy crosstalk make to aging and age-related diseases. In this review, we analyze some of the more recent findings regarding the study of brain aging and neurodegeneration in the context of mitophagy. We discuss the data on the dynamics of selective autophagy in neurons and glial cells during aging and in the course of neurodegeneration, focusing on three mechanisms of mitophagy: non-receptor-mediated mitophagy, receptor-mediated mitophagy, and transcellular mitophagy. We review the role of mitophagy in neuronal/glial homeostasis and in the molecular pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and other disorders. Common mechanisms of aging and neurodegeneration that are related to different mitophagy pathways provide a number of promising targets for potential therapeutic agents.

Mitochondrial dynamics significantly play a major role in the pathogenesis of neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. The dysregulation of mitochondrial biogenesis and function, characterized by impaired fission and fusion processes mediated by a number of proteins, in particular, Drp1, Mfn1, Mfn2, Opa1, and PGC-1α, contributes to neuronal vulnerability and degeneration. Insufficient mitophagy and disrupted mitochondrial transport exacerbate oxidative stress and neurotoxicity. Emerging therapeutic strategies that target mitochondrial dynamics, including various pharmacological agents, demonstrate potential for restoring mitochondrial balance and enhancing neuroprotection. This growing body of research underscores the importance of mitochondrial health in developing effective interventions for neurodegenerative conditions. This review highlights well-established links between the disruption of mitochondrial dynamics and the development of neurodegenerative processes. We also discuss different therapeutic strategies that target mitochondrial function in neurons that have been proposed as perspective neuroprotective treatments.

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Some cases of PD may be caused by genetic factors, among which mutations in the LRRK2 and SNCA genes play an important role. To develop effective neuroprotective strategies for PD, it is important to diagnose the disease at the earliest stages of the neurodegenerative process. Therefore, the detection of diagnostic and prognostic markers of Parkinson’s disease (PD) is an urgent medical need. Advances in induced pluripotent stem cell (iPSC) culture technology provide new opportunities for the search for new biomarkers of PD and its modeling in vitro. In our work, we used a new technology for multiplex profiling of gene expression using barcoding on the Nanostring platform to assess the activity of mitochondrial genes on iPSC-derived cultures of dopaminergic neurons obtained from patients with LRRK2- and SNCA-associated genetic forms PD and a healthy donor. Electron microscopy revealed ultrastructural changes in mitochondria in both LRRK2 and SNCA mutant cells, whereas mitochondria in cells from a healthy donor were normal. In a culture with the SNCA gene mutation, the ratio of the area occupied by mitochondria to the total area of the cytoplasm was significantly lower than in the control and in the line with the LRRK2 gene mutation. Transcriptome analysis of 105 mitochondria proteome genes using the Nanostring platform revealed differences between the diseased and normal cells in the activity of genes involved in respiratory complex function, the tricarboxylic acid cycle, ATP production, mitochondria–endoplasmic reticulum interaction, mitophagy, regulation of calcium concentration, and mitochondrial DNA replication.

Accumulating data suggest that the brain undergoes various changes during aging. Among them are loss of both white and gray matter, neurons and synapses degeneration, as well as oxidative, inflammatory, and biochemical changes. The above-mentioned age-related features are closely related to autophagy and mitochondria. Therefore, we aimed to reveal the most peculiar morphological features of brain nervous tissue and to characterize the expression of autophagy and mitochondrial immunohistochemical biomarkers in neurons of different human brain zones during aging. Counting the number of neurons as well as Microtubule-associated proteins 1A/1B light chain 3B (LC3B), Heat shock protein 70 (HSP70), Lysosome-associated membrane protein type 2A (LAMP2A), Alpha subunit of ATP synthase (ATP5A), and Parkinson disease protein 7 (DJ1) immunohistochemical staining were performed on FFPE samples of human prefrontal cortex, corpus striatum, and hippocampus obtained from autopsy. Statistical analysis revealed a loss of neurons in the studied elderly group in comparison to the young group. When the expression of macroautophagy (LC3B), chaperon-mediated autophagy (HSP70, LAMP2A), and mitochondrial respiratory chain complex V (ATP5A) markers for the young and elderly groups were compared, the latter was found to have a significantly higher rate of optical density, whilst there was no significance in DJ1 expression. These findings, while preliminary, suggest that both autophagy and mitochondria are involved in neuronal maintenance during aging and could indicate their potential role in adaptive mechanisms that occur in aging.