ABSTRACT
BACKGROUND: Allgrove disease is a rare genetic syndrome characterized by adrenal insufficiency, alacrimia, achalasia and complex neurological involvement. Allgrove disease is due to recessive mutations in the AAAS gene, which encodes for the nucleoporin Aladin, implicated in the nucleocytoplasmic transport. The adrenal insufficiency has been suggested to rely on adrenal gland-ACTH resistance. However, the link between the molecular pathology affecting the nucleoporin Aladin and the glucocorticoid deficiency is still unknown. RESULTS: By analyzing postmortem patient's adrenal gland, we identified a downregulation of Aladin transcript and protein. We found a downregulation of Scavenger receptor class B-1 (SCARB1), a key component of the steroidogenic pathway, and SCARB1 regulatory miRNAs (mir125a, mir455) in patient's tissues. With the hypothesis of an impairment in the nucleocytoplasmic transport of the SCARB1 transcription enhancer cyclic AMP-dependent protein kinase (PKA), we detected a reduction of nuclear Phospho-PKA and a cytoplasmic mislocalization in patient's samples. CONCLUSIONS: These results shed a light on the possible mechanisms linking ACTH resistance, SCARB1 impairment, and defective nucleocytoplasmic transport.
Subject(s)
Adrenal Insufficiency , Esophageal Achalasia , MicroRNAs , Humans , Esophageal Achalasia/genetics , Esophageal Achalasia/metabolism , Esophageal Achalasia/pathology , Nuclear Pore Complex Proteins/genetics , Nuclear Pore Complex Proteins/metabolism , Down-Regulation/genetics , Nerve Tissue Proteins/genetics , Adrenal Insufficiency/genetics , Adrenal Insufficiency/metabolism , Adrenal Insufficiency/pathology , Nuclear Proteins/genetics , Scavenger Receptors, Class B/genetics , Scavenger Receptors, Class B/metabolismABSTRACT
In the ongoing process of uncovering molecular abnormalities in neurodegenerative diseases characterized by toxic protein aggregates, nucleo-cytoplasmic transport defects have an emerging role. Several pieces of evidence suggest a link between neuronal protein inclusions and nuclear pore complex (NPC) damage. These processes lead to oxidative stress, inefficient transcription, and aberrant DNA/RNA maintenance. The clinical and neuropathological spectrum of NPC defects is broad, ranging from physiological aging to a suite of neurodegenerative diseases. A better understanding of the shared pathways among these conditions may represent a significant step toward dissecting their underlying molecular mechanisms, opening the way to a real possibility of identifying common therapeutic targets.
Subject(s)
Active Transport, Cell Nucleus/physiology , Cell Nucleus/metabolism , Neurodegenerative Diseases/metabolism , Protein Aggregates/physiology , Animals , Cell Nucleus/genetics , Cell Nucleus/pathology , Humans , Inclusion Bodies/genetics , Inclusion Bodies/metabolism , Inclusion Bodies/pathology , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/pathology , Nuclear Pore/genetics , Nuclear Pore/metabolism , Nuclear Pore/pathology , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolismABSTRACT
Mutations in the gene encoding the mitochondrial carrier protein SLC25A46 are known to cause optic atrophy associated with peripheral neuropathy and congenital pontocerebellar hypoplasia. We found novel biallelic SLC25A46 mutations (p.H137R, p.A401Sfs*17) in a patient with Parkinson's disease and optic atrophy. Screening of six unrelated patients with parkinsonism and optic atrophy allowed us to identify two additional mutations (p.A176V, p.K256R) in a second patient. All identified variants are predicted likely pathogenic and affect very conserved protein residues. These findings suggest for the first time a possible link between Parkinson's Disease and SLC25A46 mutations. Replication in additional studies is needed to conclusively prove this link.
Subject(s)
Mitochondrial Proteins/genetics , Optic Atrophy/genetics , Parkinson Disease/genetics , Phosphate Transport Proteins/genetics , Adult , Aged , Female , Humans , Male , Mutation , Optic Atrophy/diagnosis , Parkinson Disease/diagnosis , PedigreeABSTRACT
Allgrove syndrome (AS) is a rare disease with broad neurological involvement. Neurodegeneration can affect spinal motor neurons, Purkinje cells, striatal neurons and the autonomic system. The mechanisms that lead to neuronal loss are still unclear. Recessive mutations in the AAAS gene affect the encoded protein Aladin, which would normally localize to the cytoplasmic face of the nuclear membrane as part of the nuclear pore complex (NPC). While the NPC is known to be a key factor for nucleocytoplasmic transport, the precise role of Aladin has not been elucidated yet. Here, we explored the consequences of the homozygous AAAS mutation c.464G>A (p.R155H) in central nervous system tissues and fibroblasts of a novel AS patient presenting motor neuron disease, cerebellar ataxia and autonomic dysfunction. Neuropathological analyses showed severe loss of motor neurons and Purkinje cells, with significant reduction in the perinuclear expression of Aladin. A reduced amount of protein was detected in the nuclear membrane fraction of the patient's brain. RNA analysis revealed a significant reduction of the transcript AAAS-1, while the AAAS-2 transcript was upregulated in fibroblasts. To our knowledge, this is the first study to demonstrate the effects of AAAS mutations in the human central nervous system.
