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Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. These structures are essential for the development of many tissues and organs, however, their function in adult tissues, particularly neurons in the brain, remains largely unknown. Tau tubulin kinase 2 (TTBK2) is a critical regulator of ciliogenesis, and is also mutated in a hereditary neurodegenerative disorder, spinocerebellar ataxia type 11 (SCA11). Here, we show that conditional knockout of in adult mice results in degenerative cerebellar phenotypes that recapitulate aspects of SCA11 including motor coordination deficits and defects to Purkinje cell (PC) integrity. We also find that the conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking gene in adult mice results in nearly identical cerebellar phenotypes to those of the knockout, indicating that disruption of ciliary signaling is a key driver of these phenotypes. Our data suggest that primary cilia play an integral role in maintaining the function of PCs in the adult cerebellum and reveal novel insights into mechanisms involved in neurodegeneration.
This article was published in the following journal.
Appropriate axonal growth and connectivity are essential for functional wiring of the brain. Joubert syndrome-related disorders (JSRD), a group of ciliopathies in which mutations disrupt primary cilia...
During postnatal development, cerebellar climbing fibers alter their innervation strengths onto supernumerary Purkinje cell targets, generating a one-to-few connectivity pattern in adulthood. To get i...
Up-regulated HIF-2α (hypoxia induced factor 2) had been demonstrated to contribute to Osteoarthritis (OA) development via inducing the expression of matrix-degrading enzymes. However, the HIF-2α als...
There is growing evidence of altered connectivity in autism spectrum disorders (ASD) between the cerebellum and cortex. Three intrinsic connectivity networks (ICNs) are especially important to cogniti...
Primary cilia function as cellular signaling hubs, integrating multiple signaling pathways. Patients with the ciliopathy Joubert syndrome have been suggested to have axonal tract defects. In this issu...
The hereditary cerebellar ataxias include diverse neurodegenerative disorders. Hereditary ataxias can be divided into autosomal dominant ataxias (ADCAs), autosomal recessive ataxias (ARCAs...
Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is ...
Neurodegenerative cerebellar ataxias represent a group of disabling disorders which currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-i...
Cerebellar ataxia is a form of ataxia originating in the cerebellum. Cerebellar ataxia can occur as a result of many diseases and may present with symptoms of an inability to coordinate ba...
Cigarette smoking is the major risk factor for developing chronic obstructive pulmonary disease (COPD). Patients with COPD have difficulty clearing mucus and debris from their airways. Eve...
Cerebellar degeneration associated with a remote neoplasm. Clinical manifestations include progressive limb and GAIT ATAXIA; DYSARTHRIA; and NYSTAGMUS, PATHOLOGIC. The histologic type of the associated neoplasm is usually carcinoma or lymphoma. Pathologically the cerebellar cortex and subcortical nuclei demonstrate diffuse degenerative changes. Anti-Purkinje cell antibodies (anti-Yo) are found in the serum of approximately 50% of affected individuals. (Adams et al., Principles of Neurology, 6th ed, p686)
Primary or metastatic neoplasms of the CEREBELLUM. Tumors in this location frequently present with ATAXIA or signs of INTRACRANIAL HYPERTENSION due to obstruction of the fourth ventricle. Common primary cerebellar tumors include fibrillary ASTROCYTOMA and cerebellar HEMANGIOBLASTOMA. The cerebellum is a relatively common site for tumor metastases from the lung, breast, and other distant organs. (From Okazaki & Scheithauer, Atlas of Neuropathology, 1988, p86 and p141)
The output neurons of the cerebellar cortex.
A glutamate plasma membrane transporter protein that is primarily expressed in cerebellar PURKINJE CELLS on postsynaptic DENDRITIC SPINES.
An ataxin that is associated with the survival of cerebellar neurons. Expansion of the ATTCT pentanucleotide in the ATXN10 coding region is associated with SPINOCEREBELLAR ATAXIA 10.
Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...