A FUNCTIONAL CHARACTERIZATION OF SPG7 AND ITS RELATION TO KIF1C IN ACCELERATING NEURODEGENERATION IN CHILDHOOD HEREDITARY SPASTIC PARAPLEGIA

Abstract

Hereditary Spastic Paraplegia (HSP) is a complex heterogeneous group of rare neurodegenerative disorders that has a wide range of variability in its clinical manifestations, genetic background and implicated pathophysiology. HSP’s main distinguishing sign is axonal degeneration of corticospinal neurons that control voluntary muscle movement, and its distinctive symptom is progressive spasticity and contraction in the lower limbs._x000D_ _x000D_ This manuscript attempts to describe the mechanism of action behind the symptoms of a young girl of 2.5 years who presented with lupus and various neurologic symptoms that could not be diagnosed clinically. Following whole exome sequencing, 2 candidate missense variants were suggested to be causative of the early onset spastic paraparesis of patient MND 37.01. The first is a novel variant of paraplegin (SPG7), which is required for the assembly of hexameric m-AAA proteases in the inner mitochondrial membrane. This complex plays a crucial role in the regulation of the mitochondrial metabolic profile. The mutation falls in the AAA-ATPase domain required for ATP hydrolysis. The second candidate is a variant of kinesin family member 1C (KIF1C). This mutation falls near the 14-3-3 domain which is a Phospho-Ser/Thr binding domain. KIF1C is involved in anterograde and retrograde transport between the ER and Golgi, membrane trafficking and membrane wrapping of oligodendrocytes along axons which greatly affects the myelin sheath of motor neurons. _x000D_ _x000D_ First the missense variants were confirmed with sanger sequencing. Then, to understand the mechanism of action that led to hereditary spastic paraplegia in MND 37.01, many experimental procedures were employed. The experiments performed were aimed to investigate change in expression of the variant proteins and change in two functions of paraplegin, which are protein maturation and regulation of oxidative phosphorylation through maintaining stability of respiratory complexes I and III. _x000D_ _x000D_ The proposed explanation of the severe phenotype observed in MND 37.01, is that due to the redundancy of both SPG7 and KIF1C, it was the collective effect of both their mutations and the genetic background of the patient that lead to the neurological phenotype. Both the reduced metabolic ability of the mitochondria and the change in membrane trafficking, led to axonal degeneration which presented itself as HSP.

Date of Award	2020
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences