FBR: Dra. Ángela Nieto

THE FUTURE OF BIOMEDICAL RESEARCH

Speaker: Dra. Ángela Nieto
Universidad Pablo de Olavide-CSIC
Place: Salón de Actos CIPF

Abstract: Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited
neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive
dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal
degeneration. The most prevalent form of NBIA is pantothenate kinase-associated
neurodegeneration (PKAN) associated with mutations in the gene of pantothenate kinase 2
(PANK2), which is essential for coenzyme A (CoA) synthesis. There is no cure for NBIA nor is there
a standard course of treatment. In our work, we have demnonstrated that fibroblasts derived
from patients harbouring PANK2 mutations can reproduce many of the cellular pathological
alterations found in the disease, such as intracellular iron and lipofuscin accumulation, increased
oxidative stress, and mitochondrial dysfunction. Furthermore, mutant fibroblasts showed a
characteristic senescent morphology. Treatment with pantothenate, the PANK2 enzyme
substrate, was able to correct all pathological alterations in responder mutant fibroblasts with
residual PANK2 enzyme expression. However, pantothenate had no effect on mutant fibroblasts
with truncated/incomplete protein expression. The positive effect of pantothenate in particular
mutations was also confirmed in induced neurons obtained by direct reprograming of mutant
fibroblasts. Our results suggest that pantothenate treatment can stabilize the expression levels
of PANK2 in selected mutations. These results encourage us to propose our screening model as
a quick and easy way to detect pantothenate-responder patients with PANK2 mutations. The
existence of residual enzyme expression in some affected individuals raises the possibility of
treatment using high dose of pantothenate.