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Alzheimer's disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our cross-phenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD.

Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD. In this study, we identified LONP1, an ATP-dependent protease in the matrix, as a top Aβ42 interacting mitochondrial protein through an unbiased screening and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m6 A signaling contributed at least in part to Aβ42-induced LONP1 reduction. Moreover, Aβ42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aβ and in the brain of CRND8 APP transgenic mice rescued Aβ-induced mitochondrial deficits and cognitive deficits. These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a mechanism underlying intracellular Aβ42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence links Alzheimer's disease (AD) to dysfunction of the primary cilium, a historically overlooked organelle that serves as the neuron's antenna. All neurons harbor a single primary cilium that projects from the membrane to sense changes in the extracellular environment. Primary cilia dysfunction leads to a group of diseases called 'ciliopathies', which are associated with reduced hippocampal and cortical mass, as well as neurocognitive impairment. Ciliopathies place individuals at higher risk for dementia, and genetic defects in primary cilia proteins in mice lead to a phenotype resembling AD. Method: To establish whether primary cilia are disrupted in AD, we conducted unbiased analysis of differentially expressed genes (DEGs) in postmortem brains from AD subjects, compared to age‐matched non‐AD controls. Using the DAVID bioinformatics platform, we performed a gene ontology analysis on the significantly changed genes related to the primary cilia. Additionally, we performed immunohistochemical and electron microscopy analysis of primary cilia in the brains of 5xFAD mice, a mouse model of AD. Primary cilia were visualized with antibodies to adenylate cyclase 3 (AC3). Result: Our systematic survey of the published literature in AD revealed very few studies to date of cilia, compared to other organelles. Our analysis of DEGs in postmortem human AD brains revealed a high prevalence of DEGs intricately linked to processes that maintain primary cilia structure and function. Furthermore, the proportion of DEGs related to the primary cilia was comparable to that observed in other heavily implicated organelles in AD, such as mitochondria. Additionally, we found that the gene ADCY3, which encodes for primary cilia‐specific adenylate cyclase 3 (AC3), is significantly downregulated in human AD brains. Primary cilia are dependent on AC3, and loss of functional AC3 in primary cilia reveals consequences reminiscent of symptoms associated with AD. We observed reduced levels of AC3 throughout the hippocampus of 5xFAD mice. Additionally, electron microscopy analysis of primary cilia revealed shortened primary cilia length in advanced stages of disease in 5xFAD mice. Conclusion: AC3 loss and primary cilia deterioration may drive progression of AD pathology and provide a basis for development of a new neuroprotective therapy for AD. [ABSTRACT FROM AUTHOR]

Genetic mutations in TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria- transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43- induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration., ALS is the most common motor disease characterized by progressive motor neuron degeneration in the brain stem and spinal cord (1), and FTD is the second-most common form of early-onset [...]

Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson's disease (PD), and increasing evidence suggests abnormal mitochondrial dynamics and quality control as important underlying mechanisms. The VPS35 gene, which encodes a key component of the membrane protein-recycling retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations lead to neurodegeneration remains unclear. Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo and in human fibroblasts from an individual with PD who has the [VPS35.sup.D620N] mutation. VPS35-induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. Notably, oxidative stress increased the VPS35-DLP1 interaction, which we also found to be increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is probably involved in the pathogenesis of familial, and possibly sporadic, PD., Mitochondria are dynamic organelles that undergo continual fission and fusion events that are regulated by large GTPases, such as DLP 1 for fission and mitofusin 2 (MFN2) for fusion (1). [...]

Mitochondrial homeostasis is critical for tissue health, and mitochondrial dysfunction contributes to numerous diseases, including heart failure. Here, we have shown that the transcription factor Kruppel-like factor 4 (KLF4) governs mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Adult mice with cardiac-specific Klf4 deficiency developed cardiac dysfunction with aging or in response to pressure overload that was characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial shape, size, ultrastructure, and alignment. Evaluation of mitochondria isolated from KLF4-deficient hearts revealed a reduced respiration rate that is likely due to defects in electron transport chain complex I. Further, cardiac- specific, embryonic Klf4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. We determined that KLF4 binds to, cooperates with, and is requisite for optimal function of the estrogen-related receptor/PPARγ coactivator 1 (ERR/PGC-1) transcriptional regulatory module on metabolic and mitochondrial targets. Finally, we found that KLF4 regulates autophagy flux through transcriptional regulation of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis., Introduction The heart has an unrelenting need for energy throughout life to sustain contractile function. Despite its high-energy demand, the heart contains relatively low ATP reserves, and thus, a continual [...]