have been found in multiple patients with brain disorders of a similar phenotype including hypotonia, developmental delay, movement disorders, and seizure or seizure-like movements. This spectrum of brain disorders is similar to the phenotype of a central nervous system syndrome termed the 5q31.3 microdeletion syndrome, and is the basis for a proposed PURA Syndrome based on PURA mutations rather than just deletions. Influence on HIV-1 replication In the brain Pur-alpha plays a role in diseases involving glial cells, cells that support nerve cells, as well as diseases involving nerve cells. These diseases include neuro-AIDS. Pur-alpha binds to a regulatory RNA element, called TAR, in the HIV-1 genome. This activates the expression of Tat, a transcriptional activator of its own gene. Pur-alpha binds TAR, allowing Tat to bind an adjacent TAR site to stimulate transcription. Pur-alpha then binds to the Tat protein itself. Pur-alpha also binds Cyclin T1, a regulatory partner of Cdk9 protein kinase, necessary for Tat activity. Cyclin T1/Cdk9 phosphorylates a region of RNA polymerase II. Such phosphorylation of the polymerase enhances its ability to complete RNA synthesis and stimulates replication of the HIV-1 RNA genome. Cooperative effect with HIV-1 on JC polyomavirus replication and expression Pur-alpha participates in development of progressive multifocal leukoencephalopathy (PML), a loss of the nerve sheath formed by oligodendroglial cells. Although HIV-1 is not usually found in these glial cells, HIV-1 proteins can pass through cell membranes to enter them. JCV is considered the causative agent of PML. JCV is activated in the glial cells by certain states of immune system suppression, including HIV-1 infection. There is a documented interaction between Pur-alpha, the HIV-1 protein, Tat, and a Pur-alpha-binding regulatory sequence in JCV DNA. Pur-alpha acts by altering both replication and gene expression of JCV. Role in amyotrophic lateral sclerosis (ALS) Pur-alpha plays a role in ALS, otherwise known as Lou Gehrig's disease. ALS is a motor neuron disease involving both the brain and spinal cord, resulting in progressive loss of muscle control. ALS has several contributing causes, but the most common familial form is due to an expanded repeat of the hexanucleotide GGGGCC at the chromosomal locus C9ORF72. The C9ORF72 hexanucleotide repeat expansion (HRE) is capable of binding Pur-alpha very tightly. Pur-alpha may act in ALS directly by binding this DNA repeat expansion or its single-stranded RNA transcript. One potential consequence of this binding would be to influence an unconventional translation of this