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PURPOSE. Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. METHODS. Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. RESULTS. Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. CONCLUSIONS. This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.

Final publication is available at http://dx.doi.org/10.1016/j.nmd.2016.03.001 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19928号 / 医博第4148号 / 新制||医||1017(附属図書館) / 33014 / 京都大学大学院医学研究科医学専攻 / (主査)教授 萩原 正敏, 教授 羽賀 博典, 教授 松田 秀一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第18910号 / 人健博第24号 / 新制||人健||2(附属図書館) / 31861 / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 十一 元三, 教授 我部山 ｷﾖ子, 教授 平家 俊男 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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The neuromuscular junction (NMJ) exhibits an extraordinary capacity for adaptation and plasticity throughout an individual's lifespan. This remarkable adaptability assumes a central role in safeguarding optimal neuromuscular function and counteracting neurodegenerative processes commonly associated with aging and prevalent neuromuscular disorders. The plasticity of the NMJ is under the influence of its cellular constituents, including the ⍺-motoneuron and the innervated muscle fiber. Among the diverse array of regulatory molecules, AMP-activated protein kinase (AMPK) plays a pivotal role in governing the phenotype of these cellular components, thereby potentially contributing to synaptic modifications. To explore the regulatory role of AMPK on the NMJ phenotype, we undertook a comprehensive investigation encompassing transgenic, pharmacologic, and physiologic manipulations of this kinase. In Study 1, we investigated the significance of skeletal muscle AMPK during aging, revealing its necessity in preserving NMJ integrity. Moreover, we observed that pharmacological and physiological activation of AMPK result in an enhanced synaptic gene profile in young animals, suggesting its role in NMJ modulation. Building upon these insights, we validate the stimulatory effects of a pan-AMPK activator, MK-8722 (MK), in the context of a prevalent neuromuscular disorder, Duchenne Muscular Dystrophy (DMD). Our investigations demonstrated that MK effectively evoked AMPK activation and downstream signaling in dystrophic muscle, providing the experimental foundations our third study. Here, we assess of the chronic effects of daily MK treatment in a pre-clinical DMD model and revealed significant improvements in mitochondrial health, neuromuscular function, and a reduction in muscle fibrosis and fatigue. Taken together, these findings support a critical role of AMPK in neuromuscular plasticity and highlight the kinase as a promising therapeutic target for muscular dystrophy. / Dissertation / Doctor of Philosophy (PhD) / The neuromuscular junction (NMJ) plays a vital role in maintaining muscle function and countering aging and neuromuscular disorders. This thesis investigated the role of AMP-activated protein kinase (AMPK) in neuromuscular biology during conditions of health and disease. We conducted various experiments involving genetic modifications, drug treatments, and exercise. First, we determined that AMPK is necessary to maintain the NMJ during aging. Stimulation of AMPK with a potent activator, MK-8722 (MK), led to elevated NMJ-related gene expression. We then shifted our focus to the most prevalent neuromuscular disorder, Duchenne Muscular Dystrophy (DMD). Our results showed that MK activated AMPK in dystrophic mice, prompting us to further investigate the long-term effects of daily treatment in a pre-clinical DMD model. Repeated MK treatment significantly improved neuromuscular function and reduced the symptoms of DMD. Together, our comprehensive investigation demonstrates the critical role of AMPK in shaping neuromuscular plasticity during healthy and diseased conditions.

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