Module: Clinical Neuroscience
Word count: 468
Is TIP30 overexpressed in Acute MS lesions?
Multiple sclerosis (MS) is a disabling, inflammatory condition characterized by demyelination
resulting from Oligodendrocyte damage. This initially presents in a relapse-remission manner for 5-
15 years, where relapse results from demyelination and remission results from the regeneration and
differentiation of Oligodendrocyte progenitor cells (OPCs) [1]. OPCs differentiates into pre-
oligodendrocytes, which differentiate into pre-myelinating oligodendrocytes (PMO) that then
mature into myelinating Oligodendrocytes [4]. Secondary progression that manifests as irreversible
neurological damage is thought to be linked to reduced OPC maturation [6].
PMO are not found in the white matter of healthy humans and rodents. A study by Ansi Chang et al.
however, found PMO in 34 of 48 chronic MS lesions along with a significant inverse correlation
between the percentage of lesions identified with PMO and illness duration (p<0.001), suggesting a
lack of OPC migration or differentiation [1]. This is supported by Qiao-Ling Cui et al. who found a
reduction in OPCs numbers in MS lesions compared with the control white matter [5].
Several mechanisms for OPC pathology were suggested including TNF a related apoptosis [5] and
regulation of differentiation by LINGO1, Hyaluronan [4] etc. One of particular interest is NOTCH1, a
type 1 transmembrane protein that is cleaved by y-secretase and metalloproteinase to generate the
secondary messenger Notch intracellular domain (NICD). NICD translocate to the nucleus and acts on
the target genes using specific ligands to inhibit (through canonical signalling pathway) or promote
(through non canonical signalling pathway) OPC differentiation and maturation [2].
Studies investigating the removal of canonical NOTCH1 pathway in PLP+ Oligodendrocytes saw no
change in remyelination [4], however, Nakahara et al [3] investigated the non-canonical pathway in
chronic MS neurons from which he discovered that TAT-interacting protein 30 kDa (TIP30), a protein
that blocks the translocation of NICD thus preventing OPC maturation, is overexpressed in chronic
MS specimens. Identifying whether TIP30 is overexpressed in acute MS lesions, may aid the
understanding of its role in MS. Since, acute MS lesions at early stages have an enhanced ability to
remyelinate, TIP30 may not be overexpressed, however a significant positive correlation may be
seen between the duration of acute MS and the degree of TIP30 overexpression.
The aim of this study is to identify whether TIP-30 is expressed more abundantly in acute MS lesions
compared with healthy white matter.
Neurons from post-mortem brain slices belonging to 5 acute MS patients and 5 healthy patients will
be sectioned. To differentiate between myelination and demyelination, a Luxol fast blue and a
Word count: 468
Is TIP30 overexpressed in Acute MS lesions?
Multiple sclerosis (MS) is a disabling, inflammatory condition characterized by demyelination
resulting from Oligodendrocyte damage. This initially presents in a relapse-remission manner for 5-
15 years, where relapse results from demyelination and remission results from the regeneration and
differentiation of Oligodendrocyte progenitor cells (OPCs) [1]. OPCs differentiates into pre-
oligodendrocytes, which differentiate into pre-myelinating oligodendrocytes (PMO) that then
mature into myelinating Oligodendrocytes [4]. Secondary progression that manifests as irreversible
neurological damage is thought to be linked to reduced OPC maturation [6].
PMO are not found in the white matter of healthy humans and rodents. A study by Ansi Chang et al.
however, found PMO in 34 of 48 chronic MS lesions along with a significant inverse correlation
between the percentage of lesions identified with PMO and illness duration (p<0.001), suggesting a
lack of OPC migration or differentiation [1]. This is supported by Qiao-Ling Cui et al. who found a
reduction in OPCs numbers in MS lesions compared with the control white matter [5].
Several mechanisms for OPC pathology were suggested including TNF a related apoptosis [5] and
regulation of differentiation by LINGO1, Hyaluronan [4] etc. One of particular interest is NOTCH1, a
type 1 transmembrane protein that is cleaved by y-secretase and metalloproteinase to generate the
secondary messenger Notch intracellular domain (NICD). NICD translocate to the nucleus and acts on
the target genes using specific ligands to inhibit (through canonical signalling pathway) or promote
(through non canonical signalling pathway) OPC differentiation and maturation [2].
Studies investigating the removal of canonical NOTCH1 pathway in PLP+ Oligodendrocytes saw no
change in remyelination [4], however, Nakahara et al [3] investigated the non-canonical pathway in
chronic MS neurons from which he discovered that TAT-interacting protein 30 kDa (TIP30), a protein
that blocks the translocation of NICD thus preventing OPC maturation, is overexpressed in chronic
MS specimens. Identifying whether TIP30 is overexpressed in acute MS lesions, may aid the
understanding of its role in MS. Since, acute MS lesions at early stages have an enhanced ability to
remyelinate, TIP30 may not be overexpressed, however a significant positive correlation may be
seen between the duration of acute MS and the degree of TIP30 overexpression.
The aim of this study is to identify whether TIP-30 is expressed more abundantly in acute MS lesions
compared with healthy white matter.
Neurons from post-mortem brain slices belonging to 5 acute MS patients and 5 healthy patients will
be sectioned. To differentiate between myelination and demyelination, a Luxol fast blue and a
