Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion.
Loss of function mutations in progranulin cause tau-negative frontotemporal lobar degeneration with ubiquitin-positive inclusions. A major protein component of these inclusions is TDP-43, which becomes hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments, which apparently translocate from nuclei to the cytoplasm. Most progranulin mutations are nonsense mutations resulting in nonsense-mediated mRNA decay and consequently reduced progranulin protein levels. However, some missense mutations are described that occur within the signal sequence and mature progranulin. We now demonstrate that a progranulin mutation located within the signal sequence (PGRN A9D) results in cytoplasmic missorting with extremely low expression. In contrast, two other progranulin mutations (PGRN P248L and R432C) are expressed as immature proteins but are inefficiently transported through and partially degraded within the secretory pathway, resulting in a significantly reduced secretion. Thus apparently all progranulin mutations cause reduced protein expression or secretion, although by different cellular mechanisms. To investigate a putative relationship between reduced expression of progranulin and TDP-43 relocalization and deposition, we down-regulated progranulin in human cell lines and in zebrafish. Upon reduction of progranulin, neither a major redistribution of TDP-43 nor proteolytic processing to disease-characterizing C-terminal fragments could be observed.
Shankaran
Sunita S
SS
Munich Center for Integrated Protein Science and Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, 80336 Munich, Germany.
Capell
Anja
A
Munich Center for Integrated Protein Science and Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, 80336 Munich, Germany.
Hruscha
Alexander T
AT
Munich Center for Integrated Protein Science and Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, 80336 Munich, Germany.
Fellerer
Katrin
K
Munich Center for Integrated Protein Science and Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, 80336 Munich, Germany.
Neumann
Manuela
M
Center for Neuropathology and Prion Research, Ludwig-Maximilians University, 80336 Munich, Germany.
Schmid
Bettina
B
Munich Center for Integrated Protein Science and Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, 80336 Munich, Germany.
Haass
Christian
C
Munich Center for Integrated Protein Science and Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, 80336 Munich, Germany. Electronic address: chaass@med.uni-muenchen.de.
D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003704:Dementia / Q000235:genetics*; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D000077153:Progranulins; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D013347:Subcellular Fractions / Q000378:metabolism; D025801:Ubiquitin / Q000276:immunology*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D000077153:Progranulins; D025801:Ubiquitin; D029961:Zebrafish Proteins; C509430:progranulin B, zebrafish