Introduction 2005 2006 2003 2003 2007 2006 2002 2003 2006 2002 2006 1998 2000 1994 2000 2000 2000 1994 2004 2005 2006 2006 2003 2006 2005 2006 2004 2005 2002 2003 2004 2006 1996 2002 2005 2004 2002 2004 2000 2002 2002 2001 2001 2007 2001 2003 2005 2004 2006 2007 2005 2005 2006 2006 2006 2005 2005 2006 2001 This review will focus on how immunocytochemical labeling and electron microscopic analysis have helped to disclose the in situ subcellular distribution pattern of some of the key machinery proteins of the protein quality control, the organelle changes due to the presence of misfolded proteins, and the efficiency of synthetic chaperones to rescue disease-causing trafficking defects of aberrant proteins. Machinery proteins of the protein quality control reside beyond the ER 2004 2000 2002 2000 2001 1997 1996 1 1984 1982 1 1998b 1994 1995 1998a b 2 2003 2001 1986 2000 2001 2006 1997 1998 2000 1975 1987 1988 Fig. 1 Gls I Gls II  Fig. 2 a b c ER pGI GA  1 1983 1995 2003 2 2 2001 2 2 2001 2008 2000 2001 Drosophila 2002 2001 2005 2002 2001 2004 2006 The ERAD factor EDEM1 defines a novel vesicular ER exit pathway Introduction 8 1 1998a 1999 2001 2001 2001 2005 2007 2001 2003 2003 2006 1 2003 2006 2003 2007 3 2007 2007 2003 2003 2003 3 3 2007 Fig. 3 a b c e d f h arrowheads e f 2007 i  Endomannosidase assigns glucose trimming function to the Golgi apparatus 1987 1988 1990 1992 2000 4 4 1990 1992 1992 8–5  1987 2000 2000 4 4 2000 4 2003 2000 Fig. 4 a 1–3 9 2 b c d arrowheads arrows g N PM b e 2000  2006 2001 2001 2002 1996 2006 Organelle changes due to intracellular accumulation of misfolded proteins 2006 1996 2002 2005 2004 2002 2001 2005 2006 1997 2001 2003 2004 1988 1996 1998 1998 2000 1996 1992 1987 1988 Cys96Tyr 1999 5 2007 2004 1999 2002a 2002b 1999 1999 1998 1991 1995 Fig. 5 RER* Arrows RER RER* pGI 2004  1956 6 1980 2005 1992 2004 2005 6 1985 2000 1991 1985 2000 2006 1991 2002 2004 2001 2002 2007c 2004 2003 2002 2007c 2007c 2008 Fig. 6 a asterisks b  RB  2000 2000 2005 2000 7 1999 2007 1998 1999 2001 1999 1998 2003 1966 1999 1996 1999 Fig. 7 a b 2007  2000 2006 2006 2003 2006 2003 2002b 2004 2006 2002c 2001 2002a 2006 2004 2006 Synthetic chaperones for treatment of protein folding disease The various protein folding diseases mentioned above can be classified based on the pathogenetic mechanism. Efficient proteasomal degradation of the misfolded protein is characteristic of the loss-of-function pathogenesis. This is the case in protein folding diseases such as cystic fibrosis, the lung form of alpha 1-antitrypsin deficiency, aquaporin 2-caused renal diabetes insipidus, Gaucher’s disease and Fabry’s disease. Here, the missing function of the degraded protein alone can be the cause of the clinical symptoms, or secondary effects due to substrate accumulation like in lysosomal storage diseases. Intracellular accumulation due to inefficient proteasomal degradation of misfolded proteins is representative of a pathological gain-of-function mechanism, which is combined with a loss of function. Intracellular accumulation of misfolded proteins associated or not with protein aggregation can result in the activation of the unfolded protein response leading to ER stress and apoptosis. A pathological gain-of-function mechanism can be also the cause of a dominant clinical course when the wild-type protein in complexes with the mutant protein is retained inside the cells. Examples for pathological gain-of-function pathogenesis-associated protein folding diseases are myocilin-caused open-angle glaucoma, familial hypophyseal diabetes insipidus, Parkinson’s disease and Huntington’s disease. 2006 2006 2003 2006 2002 2000 2004 2004 2005 2000 1998 2007 1996 1999 2003 2002 2007b 8 8 Fig. 8 a b c d Empty columns d 2007a  2005 1999 2005 2006 2005 2006