In all cases, these proteins exhibited a general cytoplasmic localization with no evidence of nuclear inclusions (Fig.

The nuclear inclusions containing Rab24(D123I) were not cell-type specific.

The 1997 discovery that mHtt fragments misfold led to the discovery of the nuclear inclusions they cause.

The molecular mechanism underlying the formation of nuclear inclusions in cells expressing the mutant forms of Rab24 remains to be defined.

Replication in the reno-urinary epithelium is associated with viral cytopathic changes such as nuclear inclusions and decoy cells.

Sometimes the nuclear inclusion has a vesicular aspect, the chromatin may be clumped, and it may be surrounded by a halo.

Characteristic Orphan Annie eye nuclear inclusions (nuclei with uniform staining, which appear empty) and psammoma bodies on light microscopy.

The remaining cleavage reactions are catalysed by either trans-proteolytic or autoproteolytic mechanisms by the small nuclear inclusion protein (NIa-Pro).

Morphological characteristics of the nuclear inclusions Several follow-up studies supported the notion that the punctate structures containing the Rab24 mutants were inclusion bodies rather than membrane-bound organelles.

Thus, the question of whether the nuclear inclusions containing the D123I and T120A mutants are caused by dominant-negative suppression of endogenous Rab24 function remains to be resolved.

Cowdry bodies are eosinophilic nuclear inclusions composed of nucleic acid and protein seen in cells infected with Herpes simplex virus, Varicella-zoster virus, and Cytomegalovirus.

It has been proposed that SART3 target U6 to a Cajal body or a nuclear inclusion as the site of assembly of the U4/U6 snRNP.

FTLD-FUS; which is characterised by FUS positive cytoplasmic inclusions, intra nuclear inclusions, and neuritic threads.

It remains unclear whether the nuclear inclusions induced by Rab24(D123I) are generated de novo inside the nucleus or instead penetrate the nuclear membrane after being assembled in the cytoplasmic compartment.

Disruption of nuclear architecture by inclusions containing Rab24(D123I) The accumulation of nuclear inclusions in cells expressing Rab24(D123I) led to progressive degeneration of nuclear structure.

Instead of remaining in the cytoplasm in the absence of steroid, nearly all of the GR-GFP was found in the cytoplasmic and nuclear inclusion bodies containing the Rab24 mutant (Fig.

This was confirmed by TUNEL assays where cells at various stages of nuclear inclusion body accumulation showed no evidence of DNA fragmentation, either before or after disruption of the nuclear envelope (Fig.

Results Mutant forms of Rab24 accumulate in nuclear inclusions In all of the known Ras-related GTPases the guanine nucleotide binding site is surrounded by a set of highly conserved sequence elements [ 33 34 ] .

Therefore, a question raised by these studies is whether the genesis of nuclear inclusions occurs indirectly, through dominant suppression of endogenous Rab24 function by the D123I and T120A mutants, or directly, through association of cellular proteins with the accumulating mutant protein.

Ultimately, the accumulation of nuclear inclusions in cells expressing Rab24(D123I) causes a catastrophic disruption of the nuclear architecture, although this does not appear to be accompanied by classic signs of apoptotic cell death such as DNA fragmentation or caspase activation.

Discussion Here we have shown that single amino acid substitutions e.g. , D123I and T120A) in one of the conserved guanine nucleotide binding domains of Rab24 can cause the protein to accumulate in a massive array of nuclear inclusions in mammalian cells.