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| Director |
Laura Ranum |
| Phone | 352-273-6177 |
| Website | https://neurogenetics.med.ufl.edu/ |
| Mission | The mission of the Center for NeuroGenetics (CNG) is to integrate molecular, genetic and clinical research to define the causes of neurodegenerative disease that will enable the development of effective treatment strategies. The CNG will use an interdisciplinary approach to achieve its goals, combining experts in clinical and basic research with complementary skill sets. This approach will allow a rigorous investigation into the molecular causes, consequences and possible interventions for known disease that affect nervous and muscle systems as well as the identification of mutations causing novel single-gene neurogenetic disorders. |
Four RAN biomarkers not previously known to accumulate in Huntington’s disease have been discovered in a higher abundance in the brains of those affected by the disease and in early onset juvenile cases. More than 15,000 Americans have Huntington’s disease and about 150,000 others are at risk of developing the disease. Affected individuals have symptoms that include irritability, depression, involuntary jerking movements, poor coordination, trouble learning new information or making decisions, and trouble walking, speaking, and swallowing. Substantial evidence suggests that mutant huntingtin genes (HTT genes) and other expansion proteins contribute to the disease, but most treatment strategies focus on molecular readouts and attempt to reduce the only known expansion protein biomarker – polyGlutamine. Researchers at the University of Florida have discovered four proteins that accumulate in HD patients’ brains and amass in a significantly higher abundance in both affected brain regions and in juvenile onset cases. These RAN proteins are expressed by repeat-associated non-ATG translation (RAN translation) and will enable researchers to test the effectiveness of treatments and create tools to block RAN translation in HD.
Four RAN protein biomarkers enable testing for HD treatment effectiveness, allow for possible future prognosis markers, and help improve disease outcomes
Researchers have shown that polyAla, polySer, polyLeu and polyCys proteins are expressed in both the sense (positive) direction and the antisense (negative) direction in both affected brain regions and in juvenile onset cases. They are direct protein products of the mutation which are expressed in alternative reading frames without an ATG initiation codon.
Expansion of the number of repeats of a specific hexanucleotide sequence (GGGGCC, called G4C2) in the C9orf72 gene is the most common known cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). This C9-500 mouse model contains a mutation with 500 G4C2 repeats, the full human C9orf72 gene and substantial flanking sequence but no other known genes. Unlike other mouse models that overexpress G4C2 expansion mutations, or result in molecular but not pathological changes, our C9-500 mice recapitulate both the molecular and the clinical features of ALS and FTD, including progressive motor deficits and neurodegeneration.
Amyotrophic Lateral Sclerosis, also known as Lou Gehrig’s disease, is a degenerative neurological disorder leading to muscle weakness, paralysis, respiratory failure and death (Rowland and Shneider, 2001; Liu et al., 2016). In addition, the degenerative neurologic disorder FTD leads to degeneration of the frontal and anterior temporal lobes of the brain resulting in behavioral changes such as loss of empathy, apathy, and loss of inhibition (NIH, 2016). The most common known cause of both ALS and FTD is the G4C2 repeat expansion in the C9orf72 gene. The expanded repeats lead to the expression of sense G4C2 and antisense G2C4 expansion RNAs and the expression of six proteins that do not require the canonical ATG start signal previously thought to be essential for protein production (Cleary and Ranum, 2014). These six dipeptide proteins, glycine-alanine (GA), glycine-proline (GP) and glycine-arginine (GR) from the sense direction and proline-alanine (PA), proline-arginine (PR) and glycine-proline (GP) from the antisense direction, are expressed by a novel type of translation called repeat-associated non-ATG (RAN) translation. The accumulation of sense G4C2 and antisense G2C4 expansion RNAs in the cell nucleus and the accumulation of RAN proteins are consistently found in ALS/FTD patients (Zu et al. 2013, Liu et al., 2016).
Mouse model that provides unique tool for studying the cause, progression and possible treatments for ALS and FTD
