Hereditary Spastic Paraplegia

Hereditary spastic paraplegia (HSP), a genetically heterogeneous illness, is characterized by weakness, progressive and bilateral spasticity of the lower limbs, increased deep tendon reflexes, and extensor plantar responses—signs reflecting involvement of corticalsp-inal pathways. Axonal degeneration of the corticosp-inal tracts and posterior columns is a common characteristic of all types of HSP. Although this disease can be inherited as an autosomal-dominant disease (AD-HSP), an X-linked illness (X-HSP), or an autosomal-recessive disease (AR-HSP) (Table I), AD-HSP represents the majority of cases (~80%).

X-HSP has been linked to two regions of the X chromosome. At Xq28, mutations in the gene for neural cell adhesion molecule L1, an axonal glycopro-tein involved in neuronal migration and differentiation, cause one form of HSP linked to mental retardation, whereas mutations in the proteolipid protein gene at Xq21 cause another form of HSP.

A subset of autosomal-recessive cases of HSP have been shown to be homozygous for a 9.5-kb deletion involving paraplegin, a member of the AAA protein family that is homologous to several yeast mitochondria ATPases. These ATPases exhibit both proteolytic and chaperone-like activities at the inner mitochon-drial membrane. Paraplegin is localized to the inner mitochondrial membrane, and muscle biopsies from affected individuals show impairments in oxidative phosphorylation in these tissues. The AAA family of proteins possesses diverse cellular functions, including microtubule rearrangement, protein degradation, organelle biogenesis, and vesicular transport. The membrane-bound AAA proteases have been shown to possess metal-dependent peptidase activity and serve to degrade nonassembled membrane proteins. Studies of yeast have demonstrated that Ymel, a yeast homolog of paraplegin, mediates binding of substrates through the amino-terminal region of the AAA domain to degrade unfolded membrane proteins. In addition, the purified AAA domain of Ymel was shown to bind unfolded polypeptides and prevent their aggregation. These studies indicate that the chaperone-like activity of AAA proteins resides within the AAA domain.

Six AD-HSP loci have been mapped (Table I) and the locus at chromosome 2p accounts for ~ 50% of all AD-HSP pedigrees. Recently, mutations of another AAA protein, termed spastin, have been linked to a subset of AD-HSP at the chromosome 2p locus. Sequence analysis revealed various modifications of the spastin gene, including missense, nonsense, and splice site point mutations, as well as deletions and insertions. Spastin, ubiquitously expressed in both fetal and adult tissues, is thought to be an ATPase involved in the function or assembly of nuclear protein complexes. Generation of mouse models for HSP should further clarify the molecular mechanisms whereby these genetic abnormalities lead to the various types of HSP.

Conquering Fear In The 21th Century

Conquering Fear In The 21th Century

The Ultimate Guide To Overcoming Fear And Getting Breakthroughs. Fear is without doubt among the strongest and most influential emotional responses we have, and it may act as both a protective and destructive force depending upon the situation.

Get My Free Ebook

Post a comment